Morpholine derivatives

ABSTRACT

Compounds of formula (I):  
                 
         wherein A is S or O; R is H; Ar is an optionally substituted phenyl group; X is an optionally substituted phenyl group, a C 1 -C 4  alkyl, a C 3 -C 6  cycloalkyl group or a CH 2 (C 3 -C 6  cycloalkyl) group; R′ is H or C 1 -C 4  alkyl; and each R 1  is independently H or C 1 -C 4  alkyl; and pharmaceutically acceptable salts thereof are selective inhibitors of norepinephrine reuptake.

This invention relates to novel morpholine compounds, and to their usein selectively inhibiting norepinephrine reuptake.

Selective inhibition of norepinephrine reuptake is a relatively new modeof action for the treatment of affective disorders. Norepinephrineappears to play an important role in the disturbances of vegetativefunction associated with affective, anxiety and cognitive disorders.Atomoxetine hydrochloride is a selective inhibitor of norepinephrinereuptake, and is marketed for the treatment of attention deficithyperactivity disorder (ADHD). Reboxetine is also a selectivenorepinephrine reuptake inhibitor and is marketed for the treatment ofdepression. WO99/15177 discloses the use of Reboxetine to treat ADHD andWO01/01973 discloses the use of S,S-Reboxetine to treat ADHD.

According to the present invention there is provided a compound offormula (I)

wherein:

-   A is S or O;-   R is H;-   Ar is a phenyl group optionally substituted with 1, 2, 3, 4 or 5    substituents each independently selected from C₁-C₄ alkyl, O(C₁-C₄    alkyl), S(C₁-C₄ alkyl), halo, hydroxy, CO₂(C₁-C₄ alkyl), pyridyl,    thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or 5    substituents each independently selected from halo, C₁-C₄ alkyl, or    O(C₁-C₄ alkyl);-   X is a phenyl group optionally substituted with 1, 2, 3, 4 or 5    substituents each independently selected from halo, C₁-C₄ alkyl, or    O(C₁-C₄ alkyl); a C₁-C₄ alkyl group; a C₃-C₆ cycloalkyl group or a    CH₂(C₃-C₆ cycloalkyl) group;-   R′ is H or C₁-C₄ alkyl;-   each R¹ is independently H or C₁-C₄ alkyl;    -   wherein each above-mentioned C₁-C₄ alkyl group is optionally        substituted with one or more halo atoms;-   or a pharmaceutically acceptable salt thereof;-   with the proviso that, when A is O, X is a C₁-C₄ alkyl group, a    C₃-C₆ cycloalkyl group or a CH₂(C₃-C₆ cycloalkyl) group.

For the compounds of formula (I) above, it is preferred that A is S.

For the compounds of formula (I) above, it is preferred that Ar isphenyl substituted with 1, 2, 3, 4 or 5 substituents, more preferablywith 1 or 2 substituents. When Ar is a substituted phenyl, it ispreferred that not more than one of those substituents is a pyridyl,thiophenyl or optionally substituted phenyl group.

Preferred compounds of formula (I) above are those wherein Ar isortho-substituted.

In a further preferred embodiment of the present invention, there isprovided a compound of formula (Ia)

wherein:

-   R is H;-   Ar is a phenyl group;-   X is a phenyl group;-   R′ is H or C₁-C₄ alkyl;-   each R¹ is independently H or C₁-C₄ alkyl; and pharmaceutically    acceptable salts thereof.

In this further preferred embodiment, the group Ar may be substituted orunsubstituted phenyl. For example, Ar may be unsubstituted phenyl or,preferably phenyl substituted with 1, 2, 3, 4 or 5 substituents,preferably with 1 or 2, for example 1, substituent. When disubstituted,the substituted phenyl group is preferably substituted at the 2- and5-positions When monosubstituted, the substituted phenyl group ispreferably substituted in the 2-position. Suitable substituents includeC₁-C₄ alkyl, O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo, and phenyl optionallysubstituted with, for example, halo, C₁-C₄ alkyl, or O(C₁-C₄ alkyl).

In this further preferred embodiment, the group X may be substituted orunsubstituted phenyl. For example, X may be phenyl substituted with 1,2, 3, 4 or 5 substituents, preferably with 1 substituent. Suitablesubstituents include C₁-C₄ alkyl, O(C₁-C₄ alkyl), and halo.

“C₁-C₄ alkyl” as used herein includes straight and branched chain alkylgroups of 1, 2, 3 or 4 carbon atoms, and may be unsubstituted orsubstituted. C₁-C₂ alkyl groups are preferred. Suitable substituentsinclude halo. Thus the term “C₁-C₄ alkyl” includes haloalkyl. Similarterms defining different numbers of C atoms (e.g. “C₁-C₃ alkyl”) take ananalogous meaning. When R′ is C₁-C₄ alkyl it is preferablyunsubstituted. When R¹ is C₁-C₄ alkyl it is preferably unsubstituted.

“C₃-C₆ cycloalkyl” as used herein includes cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

“Halo” includes P, Cl, Br and I, and is preferably F or Cl.

“Pyridyl” as used herein includes 2-pyridyl, 3-pyridyl and 4-pyridyl.

“Thiophenyl” as used herein includes 2-thiophenyl and 3-thiophenyl.

For the compounds of formula (I) above, R′ is preferably H or Me. Morepreferably R′ is H.

For the compounds of formula (I) above, each R¹ is preferably H or Mewith 0, 1, 2 or 3 of R¹ being Me. More preferably only 1 R¹ is Me. Mostpreferably all R¹ are H.

For the compounds of formula (I) above, it is preferred that R′ and allR¹ are H.

A particularly preferred substituted C₁-C₄ alkyl group for the group Aris trifluoromethyl.

A preferred group of compounds according to the present invention isrepresented by the formula (II);

wherein

-   R₂ and R₃ are each independently selected from H, C₁-C₄ alkyl,    O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo and phenyl; and-   R₄ is selected from H and C₁-C₄ alkyl; and pharmaceutically    acceptable salts thereof.-   R₂ is preferably C₁-C₃ alkyl (especially trifluoromethyl), O(C₁-C₃    alkyl) (especially methoxy or trifluoromethoxy), F or Ph. R₃ is    preferably H. R₃ is also preferably F. R₄ is preferably H.

Compounds of the present invention are selective inhibitors ofnorepinephrine reuptake. Biogenic amine transporters control the amountof biogenic amine neurotransmitters in the synaptic cleft. Inhibition ofthe respective transporter leads to a rise in the concentration of thatneurotransmitter within the synaptic cleft. Compounds of Formula (I) andtheir pharmaceutically acceptable salts preferably exhibit a K_(i) valueless than 500 nM at the norepinephrine transporter as determined usingthe scintillation proximity assay as described below. More preferredcompounds of Formula (I) and their pharmaceutically acceptable saltsexhibit a K_(i) value less than 100 nM at the norepinephrinetransporter. More preferred compounds of Formula (I) and theirpharmaceutically acceptable salts exhibit a K_(i) value less than 50 nMat the norepinephrine transporter. Especially preferred compounds ofFormula (I) and their pharmaceutically acceptable salts exhibit a K_(i)value less than 20 nM at the norepinephrine transporter. Preferably,compounds of the present invention selectively inhibit thenorepinephrine transporter relative to the serotonin and dopaminetransporters by a factor of at least five, more preferably by a factorof at least ten. Advantageously, they have a reduced interaction (bothas substrate and inhibitor) with the liver enzyme Cytochrome P450(CYP2D6) compared with other norepinephrine-reuptake inhibitors, such asreboxetine. That is to say, they preferably exhibit less than 75%metabolism via the CYP2D6 pathway according to the CYP2D6 substrateassay described below and they preferably exhibit an IC50 of >6 μMaccording to the CYP2D6 inhibitor assay described below. They areindicated for the treatment of disorders associated with norepinephrinedysfunction in mammals, especially humans, including children,adolescents and adults.

The term “norepinephrine dysfunction” as used herein refers to areduction in the amount of norepinephrine neurotransmitter within thesynaptic cleft below that which would be considered to be normal. Thusthe phrase “disorders associated with norepinephrine dysfunction inmammals” refers to disorders which are associated with a reduction inthe amount of norepinephrine neurotransmitter within the synaptic cleftbelow that which would be considered to be normal for the mammalianspecies in question. Some examples of disorders currently believed to beassociated with reduced levels of norepinephrine within the synapticcleft are detailed below.

The compounds of the present invention are also indicated for thetreatment of disorders which are ameliorated by an increase in theamount of norepinephrine neurotransmitter within the synaptic cleft of amammal above that which would be considered to be normal for themammalian species in question.

The term “treatment” as used herein refers to both curative andprophylactic treatment of disorders associated with norepinephrinedysfunction.

Compounds of the present invention may be prepared by reacting acompound of the formula (III):

where R5 is a protecting group, e.g. benzyl, and X, R′ and R¹ are asformula (I) above and Y is a leaving group, with an aryl thiol orhydroxy aryl compound. Examples of suitable leaving groups include haloand mesylate, but the nature of the leaving group is not critical.

Compounds of the present invention may also be prepared by deprotectinga compound of the formula (IV):

where R₅ is a protecting group, e.g. benzyl, and A, Ar, X, R′ and R¹ areas defined in formula (I) above to provide a compound of formula (I),optionally followed by the step of forming a pharmaceutically acceptablesalt.

Suitable N-protecting groups will be known to the person skilled in theart as will methods for their removal. Further information on suitabledeprotecting groups is contained in the well known text “ProtectiveGroups in Organic Synthesis”, Theodora W. Greene and Peter G. M. Wuts,John Wiley & Sons, Inc., New York, 1999, pp. 494-653. PreferredN-protecting groups include benzyl, allyl, carbamates such asbenzyloxycarbonyl (cbz) and t-butyloxycarbonyl (boc) and amides.

For example, compounds of the present invention may be prepared byconventional organic chemistry techniques from N-benzyl-cyanomorpholine1 (Route A) or N-benzyl-morpholinone 2 (Route B) as outlined in Scheme 1below: For clarity, X is shown as phenyl and R′ and R¹ are shown as H.It will be appreciated that analogous methods could be applied for otherpossible identities of X, R′ and R¹.

More detail of Route A is given in Scheme 2:

The amino alcohol 4a can be obtained by reaction ofN-benzyl-cyanomorpholine 1 with a Grignard reagent, followed by acidhydrolysis to give racemic phenyl ketone 3 which may be separated onchiral HPLC. (2S)-Phenyl ketone 3a may then be reduced with DIP-Cl togive 4a in high diastereomeric excess. The amino alcohol 4a is convertedinto benzyl bromide 5a, to give the desired N-substituted aryl thiomorpholines after displacement with the requisite aryl thiol.N-substituted aryloxy morpholines may be obtained in an analogous mannerby displacement with the requisite hydroxyaryl compound. Alternatively,N-substituted aryloxy morpholines may be obtained by addition of astrong base, such as sodium hydride, to the amino alcohol 4a to form anucleophilic alkoxide followed by an S_(N)Ar reaction with an Ar groupsubstituted with a suitable leaving group (e.g. F). Deprotection of thetertiary amine gives the final products.

Detail of route B is given in Scheme 3:

Treatment of N-benzyl morpholinone 2 with a strong base such as lithiumdiisopropylamide at low temperature followed by addition of benzaldehydegives aldol adducts 6a-6d as a 2:1 mixture of diastereomer pairs 6a,6band 6c,6d, which may be separated using conventional chromatographictechniques. Reduction with a borane reagent at elevated temperaturesgives diasteremeric amino alcohol pairs 4a,4b and 4c,4d respectively.

Amino alcohol pair 4a,4b may be converted to bromide 5a,5b and furtherto racemic aryl thio morpholines as outlined in Scheme 4. Amino alcoholpair 4c,4d may be converted into the corresponding mesylate.Displacement with the requisite thiol, followed by removal of thenitrogen protecting group furnishes aryl thiol morpholines as racemicmixtures of two diastereomers. The racemic aryl thiol morpholines may beseparated into enantiomerically pure products using chiral HPLCtechnology. N-substituted aryloxy morpholines may be obtained in ananalogous manner by displacement with the requisite hydroxyarylcompound.

Aryl-substituted morpholines 33, 35, 37 may be obtained frommorpholinone 2 as outlined in Scheme 5:

An alternative route to 9 is outlined in Scheme 6. This route makes useof a chiral auxiliary and gives 9 in enantiomerically pure form.

In addition to the compounds of formula I and formula II, and processesfor the preparation of said compounds, the present invention furtherprovides pharmaceutical compositions comprising a compound of formula Ior formula II or a pharmaceutically acceptable salt thereof, togetherwith a pharmaceutically acceptable diluent or carrier.

Further, the present invention provides a compound of formula I orformula II or a pharmaceutically acceptable salt thereof, for use as apharmaceutical; and a compound of formula I or formula II or apharmaceutically acceptable salt thereof, for use as a selectiveinhibitor of the reuptake of norepinephrine.

The present compounds and salts may be indicated for the treatment ofdisorders associated with norepinephrine dysfunction in mammals,including affective, anxiety, and cognitive disorders.

Disorders associated with norepinephrine dysfunction in mammals include,for example, nervous system conditions selected from the groupconsisting of an addictive disorder and withdrawal syndrome, anadjustment disorder (including depressed mood, anxiety, mixed anxietyand depressed mood, disturbance of conduct, and mixed disturbance ofconduct and mood), an age-associated learning and mental disorder(including Alzheimer's disease), alcohol addiction, anorexia nervosa,apathy, an attention-deficit disorder (ADD) due to general medicalconditions, attention-deficit hyperactivity disorder (ADHD) includingthe predominantly inattentive type of ADHD and the predominantlyhyperactive-impulsive type of ADHD, bipolar disorder, bulimia nervosa,chronic fatigue syndrome, chronic or acute stress, cognitive disordersincluding mild cognitive impairment (MCI) and cognitive impairmentassociated with schizophrenia (CIAS), conduct disorder, cyclothymicdisorder, dementia of the Alzheimers type (DAT), depression (includingadolescent depression and minor depression), dysthymic disorder,emotional dysregulation, fibromyalgia and other somatoform disorders(including somatization disorder, conversion disorder, pain disorder,hypochondriasis, body dysmorphic disorder, undifferentiated somatoformdisorder, and somatoform NOS), generalized anxiety disorder, hypotensivestates including orthostatic hypotension, incontinence (i.e., stressincontinence, genuine stress incontinence, and mixed incontinence), aninhalation disorder, an intoxication disorder, mania, migraineheadaches, neuropathic pain, nicotine addiction, obesity (i.e., reducingthe weight of obese or overweight patients), obsessive compulsivedisorders and related spectrum disorders, oppositional defiant disorder,pain including chronic pain, neuropathic pain and antinociceptive pain,panic disorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder (i.e., premenstrual syndrome and lateluteal phase dysphoric disorder), psoriasis, psychoactive substance usedisorders, a psychotic disorder (including schizophrenia,schizoaffective and schizophreniform disorders), seasonal affectivedisorder, a sleep disorder (such as narcolepsy and enuresis), socialphobia (including social anxiety disorder), a specific developmentaldisorder, selective serotonin reuptake inhibition (SSRI) “poop out”syndrome (i.e., wherein a patient who fails to maintain a satisfactoryresponse to SSRI therapy after an initial period of satisfactoryresponse), TIC disorders (e.g., Tourette's Disease), tobacco addictionand vascular dementia. The compounds of the present invention areparticularly suitable for the treatment of attention deficithyperactivity disorder, ADHD.

Thus, the present invention also provides a compound of formula I orformula II or a pharmaceutically acceptable salt thereof for selectivelyinhibiting the reuptake of norepinephrine. Preferably such selectiveinhibition occurs within mammalian cells (including mammalian cellmembrane preparations), especially those found within the central and/orperipheral nervous system. More preferably such selective inhibitionoccurs within the cells of the central nervous system of a mammal,especially a human, in need thereof. The present invention also providesa compound of formula I or formula II or a pharmaceutically acceptablesalt thereof for treating disorders associated with norepinephrinedysfunction in mammals; and the use of a compound of formula I orformula II, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for selectively inhibiting the reuptake ofnorepinephrine; and the use of a compound of formula I or formula II, ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of disorders associated with norepinephrinedysfunction in mammals, including the disorders listed herein.

Further, the present invention provides a method for selectivelyinhibiting the reuptake of norepinephrine in mammals, comprisingadministering to a patient in need thereof an effective amount of acompound of formula I or formula II or a pharmaceutically acceptablesalt thereof; and a method for treating disorders associated withnorepinephrine dysfunction in mammals, comprising administering to apatient in need thereof an effective amount of a compound of formula Ior formula II or a pharmaceutically acceptable salt thereof.

The present invention includes the pharmaceutically acceptable salts ofthe compounds of formula I and formula II. Suitable salts include acidaddition salts, including salts formed with inorganic acids, for examplehydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, orwith organic acids, such as organic carboxylic or organic sulphonicacids, for example, acetoxybenzoic, citric, glycolic, o-mandelic-l,mandelic-dl, mandelic d, maleic, mesotartaric monohydrate,hydroxymaleic, fumaric, lactobionic, malic, methanesulphonic, napsylic,naphtalenedisulfonic, naphtoic, oxalic, palmitic, phenylacetic,propionic, pyridyl hydroxy pyruvic, salicylic, stearic, succinic,sulphanilic, tartaric, 2-hydroxyethane sulphonic, toluene-p-sulphonic,and xinafoic acids.

In addition to the pharmaceutically acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of compounds or in the preparation of other, for examplepharmaceutically acceptable, acid addition salts, or are useful foridentification, characterisation or purification.

It will be appreciated that compounds of formula I and formula IIpossess one or more asymmetric carbon atoms, and that the presentinvention is directed specifically to individual stereoisomers. Theparticular stereochemistry of the present compounds is essential to thepharmacological profile of the compounds. In the present specification,where a structural formula does not specify the stereochemistry at oneor more chiral centres, it encompasses all possible stereoisomers andall possible mixtures of stereoisomers (including, but not limited to,racemic mixtures), which may result from stereoisomerism at each of theone or more chiral centers.

The compounds of the present invention may be used as medicaments inhuman or veterinary medicine. The compounds may be administered byvarious routes, for example, by oral or rectal routes, topically orparenterally, for example by injection, and are usually employed in theform of a pharmaceutical composition.

Such compositions may be prepared by methods well known in thepharmaceutical art and normally comprise at least one active compound inassociation with a pharmaceutically acceptable diluent, excipient orcarrier. In making the compositions of the present invention, the activeingredient will usually be mixed with a carrier or diluted by a carrier,and/or enclosed within a carrier which may, for example, be in the formof a capsule, sachet, paper or other container. Where the carrier servesas a diluent, it may be solid, semi-solid, or liquid material which actsas a vehicle, excipient or medium for the active ingredient. Thus, thecomposition may be in the form of tablets, lozenges, sachets, cachets,elixirs, suspensions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,injection solutions and suspensions and sterile packaged powders.

Some examples of suitable carriers are lactose, dextrose, vegetableoils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatin, carbohydrates such as starch and petroleum jelly,sucrose sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- andpropyl-hydrobenzoate, talc, magnesium stearate and mineral oil. Thecompounds of formula (I) can also be lyophilized and the lyophilizatesobtained used, for example, for the production of injectionpreparations. The preparations indicated can be sterilized and/or cancontain auxiliaries such as lubricants, preservatives, stabilizersand/or wetting agents, emulsifiers, salts for affecting the osmoticpressure, buffer substances, colourants, flavourings and/or one or morefurther active compounds, e.g. one or more vitamins. Compositions of theinvention may be formulated so as to provide, quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures well known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage unit containing from about 5 to about 500 mg, more usually about25 to about 300 mg, of the active ingredient. The term “unit dosageform” refers to physically discrete units suitable as unitary doses forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalcarrier.

The following examples illustrate compounds of the present invention andmethods for their preparation.

EXAMPLES

Stereochemical Conventions

The absolute stereochemistry of the following compound according to thepresent invention was determined as (2S,2′S) using X-raycrystallography.

X-ray crystallographic data for the above compound is listed in Tables1-6 herein.

All of the Examples herein were obtained as single isomers eitherthrough the use of chirally pure starting material or chiral separationmethods, such as HPLC or fractional crystallization of salts formed fromchiral acids/bases.

General Synthetic Procedures for the Preparation of Examples 1-17

The numbers included in the following Sections refer to the compoundsillustrated on pages 7-10 herein.

General Procedure 1: Preparation of Racemic N-Substituted Aryl Thiols

To a solution of 5a,5b (0.02 g, 0.52 mmol) and the requisite aryl thiol(1.1 eq) in anhydrous dimethylformamide (1 ml) at room temperature undernitrogen was added cesium carbonate (1.1 eq, 0.19 g, 0.57 mmol). Thereaction mixture was heated to 95° C. for 2 hours. The reaction mixturewas allowed to cool to room temperature, diluted with ethyl acetate,then washed sequentially with water, brine, dried over magnesiumsulphate and finally concentrated in vacuo.

General Procedure 2a: Deprotection of N-Substituted Aryl Thiols

To a solution of the requisite N-benzyl aryl thiol in anhydrousdichloromethane (5 ml) was added solid supported Hünig's base (Argonaut,3.56 mmol/g, 2 eq) and α-chloroethyl chloroformate (3 to 10 eq) at roomtemperature under nitrogen. The reaction mixture was heated to 40° C.and followed by LCMS analysis. After completion the reaction mixture wasfiltered, and the resin washed with dichloromethane. The combinedorganic phases were concentrated in vacuo. Methanol (HPLC grade, 25 ml)was added and the solution heated to 60° C. for 1.5 to 4 hours. Aftercomplete consumption of starting material the methanol solution wasevaporated to give a solid which was further purified as detailed forindividual compounds.

General Procedure 2b: Deprotection of N-Substituted Aryl Thiols

To a solution of the requisite N-benzyl aryl thiol (1 eq) in ethylacetate at room temperature was added phenylchloroformate (3 eq). Themixture was warmed under reflux for 2 hours. The mixture was then cooledto room temperature and 30% NaOH with water was added over 1 hour. Thebiphasic system was stirred for 1.5 hours at room temperature and theorganic layer was separated. The organic layer was washed with water,dried over MgSO₄, filtered and rinsed with ethyl acetate.

To the mixture of carbamate and benzylchloride in ethyl acetate wasadded 5.6M dimethylamine in ethanol. The solution was warmed underreflux (70-72° C.) for 2 hours. After cooling at room temperature, waterand 12N HCl were added and the mixture was stirred for 10 minutes. Thelayers were separated and the organic phase was washed twice with water.Then the organic layer was concentrated (T=50° C.) untilcrystallization. MeOH was added and approx. 40% of solvent was thenremoved under reduce pressure, this operation was repeated. Theheterogeneous mixture was stirred for 0.5 hours at room temperature andfiltered. The precipitate was washed twice with MeOH and dried underreduce pressure at 40° C. to yield the carbamate.

To a biphasic mixture of 30% NaOH and isopropanol warmed to 65° C., wasadded the carbamate. The heterogeneous mixture was warmed under refluxfor 4 hours and then cooled to room temperature and post-agitatedovernight. The organic layer was concentrated under reduce pressure andthe yellow solid obtained was added to a mixture of AcOEt and 1N NaOH.After separation of the layers, the organic one was washed with 1N NaOH.The aqueous layers were combined and extracted with AcOEt. The combinedorganic layers were dried over MgSO₄, filtered and concentrated underreduce pressure to dryness to obtain the free amine.

General Procedure 3: Conversion of Amines into Hydrochloride Salts

To a solution of the requisite amine in dry diethyl ether (1 ml) wasadded hydrochloric acid (500 μl of a 1M solution in diethyl ether). Awhite precipitate immediately formed. The suspension was then sonicatedfor 5 minutes. Ether was blown off with a stream of nitrogen and thesamples were dried under high vacuum for several hours to give thehydrochloride salts in near quantitative yield as white solids.

General Procedure 4: Aldoladdition with Substituted Benzaldehydes

Preparation of 38a,38b; 39a,39b; 40a,40b

N-Benzylmorpholinone (1.0 eq) and the requisite aldehyde (1.1 eq) weredissolved in anhydrous tetrahydrofuran (25 ml) under nitrogen and thereaction cooled to −78° C. Then, lithium diisopropylamide (1.1 eq of a2M solution in heptane/tetrahydrofuran/ethylbenzene) was added overapproximately 20 minutes, whilst maintaining the reaction temperaturebelow −78° C. The resulting yellow solution was stirred at −78° C. for 1hour and then allowed to warm to room temperature. The reaction wasquenched with saturated ammonium chloride solution (25 ml) and extractedinto ethyl acetate. The combined organic layers were dried withmagnesium sulphate, filtered and concentrated in vacuo, to give a yellowoil which was purified by column chromatography on silica gel (eluent:ethyl acetate/hexane 70/100 [v/v]).

General Procedure 5: Reduction of Substituted Aldol Adducts

Preparation of 41a,41b; 42a,42b; 43a,43b

To a solution of the requisite amide 38a,38b, 39a,39b or 40a,40b (1.1mmol) in anhydrous tetrahydrofuran under nitrogen at room temperaturewas slowly added borane (4 eq of a 1M solution in tetrahydrofuran). Thesolution was stirred at 60° C. for 2 hours. The reaction was cooled toroom temperature; dry methanol (excess) was slowly added, followed byaqueous hydrochloric acid solution (1M, excess). The reaction mixturewas heated to 60° C. for 1 hour and quenched with aqueous potassiumcarbonate solution (1M, excess) and extracted with diethyl ether. Thecombined organic layers were washed with brine, dried with magnesiumsulphate, filtered and concentrated in vacuo yielding a yellow oil whichwas purified by column chromatography on silica gel (eluent: ethylacetate/hexane 10/100 [v/v]).

Preparation of Intermediates for the Synthesis of Examples 1-17

4-Benzylmorpholin-3-one (2)

A solution of N-benzyl-N-(2-hydroxyethyl) chloroacetamide (627.7 g, 2.76mol) in tert-butanol (0.9 l) was stirred under nitrogen while warming to25-30° C. Potassium tert-butoxide (2.897 l of a 1M solution intert-butanol, 2.90 mol, 1.05 eq) was added over 2 hours. The reactionmixture was then stirred at room temperature for 90 minutes. Ice-coldwater (6 l) was added and the resultant cloudy solution extracted withethyl acetate. The combined organic layers were washed with brine, driedover magnesium sulphate and evaporated in vacuo to give a light brownoil (441 g, 84%), which was used in the next stage without furtherpurification; MW 191.23; C₁₁H₁₃NO₂; ¹H NMR (CDCl₃): 7.29-7.40 (5H, m),4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz);LCMS: (12 min method) m/z 192 [M+H]+ @ Rt 1.00 min.

4-Benzyl-morpholine-2-carbonitrile (1)

A one-litre reactor with mechanical stirring, cooled by an ice bath, wascharged with N-benzylethanolamine (172.2 g; 1 equiv. available fromAldrich Chemical Company). 2-Chloroacrylonitrile (100 g; 1 equiv.available from Aldrich Chemical Company) was added dropwise over 2minutes. The temperature was maintained between 23° C. and 29° C. bymeans of the ice bath and subsequently a water bath at 15° C.N-Benzylethanolamine was still detected on TLC after 4.5 h stirring.After one night stirring at room temperature (water bath), noN-benzylethanolamine was detectable by ¹H NMR. The mixture was dissolvedin tetrahydrofuran and transferred to a 2 L reactor cooled to −5° C. byice/NaCl bath. The total volume of tetrahydrofuran was 1.35 L. Potassiumtert-butoxide (148 g; 1.1 equiv.) was added by portions in 1 hour,keeping the reaction temperature at 0±2° C. After 1 hour post-stirringat 0° C., the mixture was quenched with saturated NaHCO₃ (500 mL). Theaqueous layer was extracted with diethyl ether (500 mL). Organic layerswere dried on MgSO₄ and evaporated to dryness. The title compound (149.8g; 65%) was obtained after percolation of the 250 g dry residue on 1 kgof SiO₂, eluting with the following gradient:  5% AcOEt-95% n-heptane2.5 L 10% AcOEt-90% n-heptane   2 L 15% AcOEt-85% n-heptane   2 L 20%AcOEt-80% n-heptane   5 L

(2S)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone (3a) and(2R)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone (3b) Preparation viaRoute A in Scheme 1

A 31 double jacket reactor was charged with 1 (135.05 g; 1 eq) (obtainedby the method above or by the method disclosed in King, F. K.; Hadley,M. S.; Joiner, K. T.; Martin, R. T.; Sanger, G. J.; Smith, D. M.; Smith,G. E.; Smith, P.; Turner, D. H.; Watts, E. A., J. Med. Chem. 1993,36(6), 683.) and dry diethyl ether (1.4 l). Alternatively, toluene maybe used in place of diethyl ether. When Tj=0° C. and Tm=1° C.(Tj=temperature of the jacket, Tm=temperature of the mass), phenylmagnesium chloride (2M sol. in tetrahydrofuran, 360 ml, 1.08 equiv.,available from Aldrich Chemical Company) was added dropwise over 1 hour.Tm rose to 4° C. and came back to 2° C. at the end of the addition. Tmwas progressively raised to 17.5° C. within 45 minutes and the mixturestirred at this temperature for another 45 minutes. The reactor wascooled down to Tm=2° C. and Tj=0° C. (75 minutes) and hydrochloric acid(700 ml of 5N solution) was added in two portions. Tm rose to 33° C.After some minutes, the hydrochloride salt of the ketone crystallised.When Tm=Tj=room temperature, the triphasic suspension was filtered. Theorganic layer of the mother liquors, which contains impurities, waseliminated. The filtration cake was then washed with methylene chloride(700 ml). This liquor was charged in the reactor with the acid aqueouslayer. Treatment of the hydrochloride salt: After drying under vacuum,164.4 g of the hydrochloride contaminated with MgCl₂ were suspended in abiphasic mixture of water/methylenechloride (500 ml/800 ml). Thesuspension was basified with aqueous sodium hydroxide (75 ml of a 30%solution) under ice bath cooling. Mg(OH)₂ precipitated and the aqueouslayer was extracted with methylene chloride. The organic layers arefiltered on a bed of Celite 512 after adding some Celite to the layersthemselves. The filtered organic phase was dried over magnesium sulphateand evaporated to dryness. The ketone crystallizes readily on standing(132.4 g; 70%). Treatment of the mother liquors: The combined organicphases were washed with aqueous sodium hydroxide (750 ml of a 2Nsolution). Celite 512 (160 g) was added to the suspension which was thenfiltrated through a bed of Celite. The aqueous layer was separated andextracted with methylene chloride. The combined organic phases weredried over magnesium sulphate and evaporated to dryness to provide 35.8g of 3a,3b enriched with unreacted nitrile. Compound 3a was obtainedafter separation using chiral HPLC on a Daicel chiralpak AD 20 μm columnwith 100% Ethanol/0.3% DMEA as eluent at a flow rate of 150 ml/min andUV-detection at 300 nm. Alternatively, the two enantiomers may beseparated by fractional crystallization from acetonitrile using from0.55 to 1 equivalent of dibenzoyltartaric acid to generatediastereoisomeric salts of the title compound. The crystals may becollected by filtration and neutralized with 30% NaOH to afford theoptically enriched title compound.

(2S)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone (3a) and(2R)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone (3b)—One Pot Synthesis

A 1600 L GL reactor under N₂ was successively loaded with2-chloroacrylonitrile (33.2 kg, 379 moles) and toluene (114 L) at 21° C.Then, N-benzylethanolamine (57 kg, 377 moles) was added and the reactionmixture was post-agitated at room temperature for about 17 h. Then, themixture was diluted with toluene (336 L), cooled down to −12.4° C. andpotassium t-butoxide (42.3 kg, 377 moles) was added in portions (10)maintaining −13.7° C.≦Tmass≦−2.8° C. The mixture was post-agitated atabout 0° C. for 2.5 h, quenched by adding ultra pure water (142.5 L)maintaining 2.1° C.≦Tmass≦8.7° C. The aqueous layer (176 kg) wasseparated after 35 minutes of post-stirring allowing the mixture toreach 15° C. and the toluene layer was washed with ultra pure water(142.5 L) and the aqueous layer (162 kg) was separated. The organiclayer was then concentrated under reduced pressure (150 mbars)maintaining Tmass≦60° C. in order to distill 162 kg of toluene. Thefiltrates were then diluted with toluene (114 L) and treated with SiO₂(Merck silica gel 60, 0.063-0.1 mm, 74.1 kg) under agitation at roomtemperature for 1.25 h. SiO₂ was filtered and rinsed with toluene (2×114L). Then, the filtrates were concentrated under reduced pressure (150mbars) maintaining Tmass≦60° C. in order to distill 351.8 kg of toluene(KF: 0.01% w/w H₂O).

The solution of 4-Benzyl-morpholine-2-carbonitrile (169.2 kg) wasdiluted with toluene (157 L) and was cooled to 0° C. andphenylmagnesiumchloride (25 wt. % solution in THF, 213 kg, 389 moles,1.36 molar equiv.) was slowly added (over 3.5 h) to the reactionmixture, maintaining the temperature at −3° C.≦Tmass≦7° C. The reactionmixture was post-stirred for 2 hours at Tmass≈0° C. Then, the quench wasperformed by adding acetic acid (8.55 L, Tmass=5→17.2° C.), poststirring 10 minutes and cooling to 5° C. before adding an aceticacid/water mixture (229 L, 33/67 v/v). During the quench, addition wasperformed at such a rate that Tmass did not exceed 20° C. (typicalTmass=4.6° C. to 10.4° C.). The mixture was post-agitated overnight atRT and the aqueous layer (285.8 kg) was extracted.

The toluene layer was cooled to 0° C. and a 5 N NaOH aqueous solution(420.1 kg) was slowly added maintaining the temperature at −2.4°C.≦Tmass≦11° C. The reaction mixture was post-stirred for 1 h and theaqueous layer (494.8 kg) was extracted. The toluene layer wasconcentrated under reduced pressure (50 mbars) maintaining Tmass≦60° C.in order to distill 356.2 kg of toluene and isopropanol (180.4 kg) wasadded. The toluene was stripped off under reduced pressure (100 mbars)maintaining Tmass≦60° C. in order to distill 186.4 kg of toluene andisopropanol (135 kg) was added again to the mixture. A last distillationof toluene was performed under reduced pressure (50 mbars) maintainingTmass≦60° C. in order to distill 131 kg of toluene and isopropanol (49.4kg) was finally added to the mixture and the solution was stirred at RTuntil crystallization (17 minutes).

Ultra pure water was added (125.4 L) and the mixture was stirredovernight at RT and cooled down to about 0° C. for 1 hour. Theprecipitate was filtered and rinsed with a cooled water/isopropanol50/50 v/v solution (76.6 kg). The wet precipitate was dried under vacuumat Tjack=35° C. for 96 hours to obtain the title compound as anoff-white powder with 59% overall yield. The title compound may beresolved by the fractional crystallisation process described above.

(S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanol (4a)

To a stirred solution of [(−)-B-chlorodisopinocampheylborane] (45 g, 140mmol) in dry tetrahydrofuran (300 ml) under nitrogen was added 3a (7.97g, 28.4 mmol) in one portion. The reaction mixture was stirred at roomtemperature for 18 hours. The mixture was evaporated in vacuo andextracted from 2M aqueous sodium hydroxide solution into ethyl acetate.The combined organic extracts were washed with brine, dried, filteredand evaporated. The crude product was taken up in chloroform/methanol(1:1 [v/v]) and absorbed onto 150 g SCX-2 ion exchange resin. Afterelution of borane residues with methanol the product was eluted with 2Mammonia in methanol. Removal of solvent in vacuo yielded the product asyellow oil. This was further purified by flash chromatography (eluent:ethyl acetate/isohexane 80/20 [v/v]). After removal of solvents, theproduct crystallised on standing (6.73 g, 84%); MW 283.37; C₁₈H₂₁NO₂; ¹HNMR (CDCl₃): 7.32-7.45 (10H, m), 4.67 (1H, d, 7 Hz), 4.03 (1H, dt, 11 Hzand 2 Hz), 3.86-3.73 (2H, m), 3.64 (1H, d, 13 Hz), 3.39 (1H, d, 13 Hz),3.30 (1H, br, s), 2.68 (1H, d, 12 Hz), 2.56 (1H, d, 10 Hz), 2.28-2.15(2H, m); LCMS: m/z 284 [M+H]+ @ Rt 0.95 min.

(2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (5a)

To a solution of 4a (4.71 g, 16.6 mmol) in anhydrous chloroform (200 ml)under nitrogen was added triphenylphosphine dibromide (14.04 g, 33.26mmol). The reaction mixture was heated at 60° C. overnight. The mixturewas allowed to cool to room temperature then washed with saturatedaqueous sodium carbonate solution, dried over sodium sulphate andconcentrated in vacuo. The resulting residue was purified by flashchromatography on silica (eluent: ethyl acetate/isohexane gradient 10/90to 30/70 [v/v]) to give 5a as a white solid (4.63 g, 81%); MW 346.27;C₁₈H₂₀BrNO; ¹H NMR (CDCl₃): 7.14-7.39 (10H, m), 4.83 (1H, d, 7 Hz), 4.01(1H, br, t, 8 Hz), 3.73 (1H, br, d, 11 Hz), 3.60-3.48 (2H, m), 3.39 (1H,d, 12 Hz), 3.20 (1H, d, 11 Hz), 2.50 (1H, d, 10 Hz), 2.07 (2H, t, 10Hz); LCMS: (6 min method) m/z 346 [M]+ @ Rt 2.51 min.

(2S)-2-[(S)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one (6a)and (2S)-2-[(R)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one(6b) and(2R)-2-[(S)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one (6c)and (2R)-2-[(R)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one(6d)

To a stirred solution of 2 (5.02 g, 26 mmol) in anhydroustetrahydrofuran (25 ml) under nitrogen at −78° C. was added lithiumdiisopropylamide (1.5 eq, 39 mmol, 19.5 ml of a 2M solution inheptane/tetrahydrofuran/ethylbenzene) over approximately 20 minutes,whilst maintaining the reaction temperature below −75° C. The resultingbrown solution was stirred for a further 30 minutes at −78° C., beforebeing added over approximately 30 minutes to a solution of benzaldehyde(1.2 eq, 3.29 g, 31 mmol) in anhydrous tetrahydrofuran (15 ml) undernitrogen at −78° C., whilst again maintaining the reaction temperaturebelow −75° C. The resulting yellow solution was stirred at −78° C. for 1hour, before being allowed to warm to room temperature slowly over 1hour. The reaction mixture was cautiously quenched by addition ofsaturated ammonium chloride solution (50 ml) and the tetrahydrofuran wasevaporated in vacuo. The resulting cloudy aqueous solution was extractedwith dichloromethane, and the organic extracts were combined, washedwith brine, dried over sodium sulphate and the dichloromethaneevaporated in vacuo to give a thick brown oil (9.2 g), which partiallycrystallised on standing. After purification by flash columnchromatography (eluent: ethyl acetate/dichloromethane 10/90 to 20/80gradient [v/v]) 6a,6b was obtained as light red crystals (2.46 g, 32%);MW 297.36; C₁₈H₁₉NO₃; ¹H NMR (CDCl₃): 7.36-7.41 (2H, m), 7.16-7.31 (6H,m), 6.86-6.91 (2H, m), 5.14 (1H, d, 33 Hz), 4.71 (1H,d, 14 Hz), 4.48(1H, d, J 3 Hz), 4.25 (1H, d, 14 Hz), 4.20 (1H, br, s), 3.89 (1H, ddd,12 Hz, 3 Hz, 2 Hz), 3.67 (1H, dt, 11 Hz, 3 Hz), 3.16 (1H, dt, 12 Hz and4 Hz), 2.86 (1H, br, d, 12 Hz); LCMS: m/z 298 [M+H]+ @ Rt 1.24 min. 6c,6d was isolated as a brown solid (1.42 g) contaminated with 2.Trituration with ethyl acetate afforded pure 6c,6d as a white solid(0.484 g, 6%); MW 297.36; C₁₈H₁₉NO₃; ¹H NMR (CDCl₃): 7.55-7.61 (2H, m),7.36-7.50 (6H, m), 7.25-7.31 (2H, m), 5.21 (1H, d, 2 Hz), 5.09 (1H, d, J7 Hz and 2 Hz), 4.73 (2H, s), 4.37 (1H, d, J 8 Hz), 4.01 (1H, ddd, 12Hz, 3 Hz, 2 Hz), 3.77 (1H, dt, 11 Hz, 4 Hz), 3.50 (1H, dt, 12 Hz, 4 Hz),3.16 (1H, br, d, 12 Hz); LCMS: m/z 298 [M+H]+ @ Rt 1.24 min.

(S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanol (4a) and(R)-Phenyl[(2R)-4-(phenylmethyl)morpholin-2-yl]methanol (4b)

To a solution of 6a,6b (0.033 g, 1.1 mmol) in anhydrous THF (5 ml) undernitrogen at room temperature was slowly added borane (4 eq, 4.4 ml of a1M solution in tetrahydrofuran, 4.4 mmol). The solution was stirred at60° C. for 2 hours. After cooling down to room temperature, dry methanol(2 ml) was slowly added to quench excess borane reagent. After additionof aqueous hydrochloric acid solution (2 ml of a 1M solution) thereaction mixture was heated to 60° C. for 1 hour. The organic solventswere evaporated in vacuo and the concentrated solution was poured ontoaqueous potassium carbonate solution (10 ml of a 1M solution) andextracted with diethyl ether (2×20 ml). The combined organic layers werewashed with brine, water, dried over magnesium sulphate and concentratedin vacuo. Purification by flash column chromatography (eluent:hexane/ethyl acetate/triethylamine 90/9/1 [v/v/v]) gave a viscous oil(0.19 g, 60%); MW 283.37; C₁₈H₂₁NO₂; ¹H NMR (CDCl₃): 7.45-7.32 (10H, m),4.67 (1H, d, 7 Hz), 4.03 (1H, dt, 11 Hz, 2.7 Hz), 3.86-3.73 (2H, m),3.64 (1H, d, 13 Hz), 3.39 (1H, d, 13 Hz), 3.30 (1H, br, s), 2.68 (1H, d,13 Hz), 2.56 (1H, d, 11 Hz), 2.28-2.15 (2H, m); LCMS: m/z 284 [M+H]+ @Rt 0.95 min.

(R)-[(2S)-4-Benzylmorpholinyl](phenyl)methanol (4c) and(S)-[(2R)-4-Benzylmorpholinyl](phenyl)methanol (4d)

Using the procedure described for the preparation of 4a,4b starting from6c,6d (0.14 g, 0.45 mmol) 4c,4d was obtained as a viscous oil (0.098 g,68%); MW 283.37; C₁₈H₂₁NO₂; ¹H NMR (CDCl₃): 7.17-7.28 (10H, m), 4.80(1H, d, 4 Hz), 3.88 (1H, dt, 11 Hz, 3 Hz), 3.72 (1H, m), 3.61-3.68 (1H,m), 3.50 (1H, d, 13 Hz), 3.25 (1H, d, 13 Hz), 2.52 (2H, br, t, 12 Hz),2.17 (1H, t, 11 Hz), 2.08 (1H, td, 11 Hz, 3 Hz); LCMS: m/z 284 [M+H]+ @Rt 0.98 min.

(2S)-2-[(R)-Bromo(phenyl)methyl]-4-phenylmethyl)morpholine (5a) and(2R)-2-[(S)-Bbromo(phenyl)methyl]-4-(phenylmethyl)morpholine (5b)

To a solution of 4a,4b (10.27 g, 36.29 mmol) in anhydrousdichloromethane (150 ml) under nitrogen at room temperature was addedfreshly recrystallised triphenylphosphine (13.32 g, 50.80 mmol, 1.4 eq)followed by carbon tetrabromide (16.85 g, 50.8 mmol, 1.4 eq) as asolution in anhydrous dichloromethane (50 ml). After 15 minutes thereaction mixture was diluted with dichloromethane (100 ml) and washedwith saturated aqueous solution of sodium hydrogencarbonate, brine,dried over magnesium sulphate and concentrated in vacuo to give anorange oil (42.0 g). To the orange oil was added diethyl ether (200 ml)and the resulting suspension was sonicated for 30 minutes. The solventwas decanted and the process repeated with a further portion of diethylether. The combined organic extracts were concentrated in vacuo to yieldan orange solid (22.0 g) which was purified by flash columnchromatography (eluent: ethyl acetate/hexane/triethylamine 10/89.5/0.5[v/v/v]) 5a,5b was otained as a white solid (7.20 g, 57%). AlternativeWork-up: The reaction mixture was poured onto a silica (160 g)filtration pad which was washed with dichloromethane (14×250 ml). Afterremoval of solvents in vacuo and purification by flash columnchromatography (eluent: ethyl acetate/hexane/triethylamine gradient5/94.5/0.5 to 10/89.5/0.5 [v/v/v]) to give a white solid (6.05 g, 48%);MW 346.27; C₁₈H₂₀BrNO; ¹H NMR (CDCl₃): 7.14-7.39 (10H, m), 4.83 (1H, d,7 Hz), 4.01 (1H, br, t, 8 Hz), 3.73 (1H, br, d, 11 Hz), 3.48-3.60 (2H,m), 3.39 (1H, d, 12 Hz), 3.20 (1H, d, 11 Hz), 2.50 (1H, d, 10 Hz), 2.07(2H, t, 11 Hz); LCMS: m/z 348/346 [M+H]+ @ Rt 1.20 min.

4-[(1R)-1-Phenylethyl]morpholine-(2S)-carbonitrile (47a) and4-[(1R)-1-Phenylethyl]morpholine-(2R)-carbonitrile (47b)

To (R)-(−)-2-hydroxyethyl-α-phenethylamine (1.65 g, 10.0 mmol) indiethyl ether (10 ml) was added at room temperature2-chloroacrylonitrile (0.80 ml, 10.0 mmol) with stirring. The mixturewas stirred at room temperature for 4.5 days when additional2-chloroacrylonitrile (0.8 ml, 10.0 mmol) was added. After stirringanother 3.5 days, the reaction mixture was concentrated in vacuo to givean oil. The oil was dissolved in dry tetrahydrofuran (30 ml), cooledunder nitrogen to 0° C. and potassium tert-butoxide (1.23 g, 11.0 mmol)added. The solution was stirred at 0° C. for 2 hours then at reflux for1.5 hours, cooled, diluted with diethyl ether and washed with aqueoussaturated sodium bicarbonate. The organic phase was extracted with 2Nhydrochloric acid and the aqueous made basic by addition of solid sodiumbicarbonate and extracted with diethyl ether. The organic phase wasdried over magnesium sulphate, filtered and evaporated to a brown oil.The crude product was purified by flash chromatography (eluent: ethylacetate/hexane gradient 100% ethyl acetate to 50/50 [v/v]) to give47a,47b as a colourless oil (0.58 g, 27%%); MW 216.29; C₁₃H₁₆N₂O; ¹H NMR(CDCl₃) 7.25-7.38 (5H, m), 4.6 (1H, dd), 4.54 (1H, dd), 3.91-4.06 (2H,m), 3.66-3.82 (2H, m), 3.39-3.49 (2H, m), 2.30-2.89 (4H, m), 1.39 (3H,d). m/z [M+H]⁺ 217.

Phenyl{(2S)-4-[(1R)-1-phenylethyl]morpholin-2-yl}methanone (48a) andPhenyl{(2R)-4-[(1R)-1-phenylethyl]morpholin-2-yl}methanone (48b)

To a stirred solution of 47a,47b (0.57 g, 2.64 mmol) in drytetrahydrofurane (10 ml) at 0° C. under nitrogen was added a solution ofphenylmagnesium chloride in tetrahydrofurane (2.0 M, 2.67 ml) dropwiseover 2 minutes. The pale yellow solution was stirred at 0° C. for 30minutes and then allowed to warm to room temperature. After 2 hours themixture was cooled, quenched with 2M hydrochloric acid and was stirredvigorously for 1 hour at room temperature. After addition of water andextraction with ethyl acetate, the combined organic layers were washedwith brine, dried over magnesium sulphate, filtered and evaporated togive an oil (0.63 g). After purification by column chromatography(eluent: ethyl acetate/hexane gradient 0/100 to 20/80 [v/v]) 48a wasobtained as an oil (0.15 g, 19%%); MW 295.38; C₁₉H₂₁NO₂; ¹H NMR (CDCl₃)8.00 (2H, d), 7.60 (1H, t), 7.50 (2H, t), 7.20-7.35 (5H, m), 4.96 (1H,d), 3.93-4.00 (1H, m), 3.70-3.80 (1H, m), 3.41 (1H, q), 3.25 (1H, br,d), 2.59 (1H, br, d), 2.13-2.36 (2H, m), 1.38 (3H, d). m/z [M+H]⁺ 296followed by 48b as an oil (0.27 g, 35%%) ¹H NMR (CDCl₃) 7.90 (2H, d),7.54 (1H, t), 7.45 (2H, t), 7.20-7.38 (5H, m), 4.85 (1H, d), 4.05-4.12(1H, m), 3.80-3.92 (1H, m), 3.43 (1H, q), 2.86-3.00 (2H, m), 2.29-2.40(1H, m), 2.21 (1H, t), 1.38 (3H, d). m/z [M+H]⁺ 296.

(R)-Phenyl{(2S)-4-[(1R)-1-phenylethyl]morpholin-2-yl}methanol (50)

To a stirred solution of 48a (0.08 g, 0.26 mmol) and triphenylsilane(0.34 g, 1.31 mmol) in dichloromethane (4 ml) cooled to 0° C. was addedboron trifluoride etherate (0.09 g, 0.66 mmol) followed bytrifluoroacetic acid (0.36 ml, 63 mmol). The reaction mixture wasallowed to warm to room temperature and diluted after three hours withdichloromethane (20 ml) and neutralised with aqueous sodium bicarbonate.The organic phase was dried over magnesium sulphate, filtered andevaporated to give the required product. This was purified as itshydrochloric acid salt crystallising from isopropanol and diethyl ether(0.05 g, 69%%); MW 297.4; C₁₉H₂₃NO₂; ¹H NMR (CDCl₃) on free base7.08-7.29 (10H, m), 4.78 (1H, d), 3.90-4.00 (1H, m), 3.57-3.68 (2H, m),3.33 (1H, q), 2.53-2.64 (1H, m), 2.37-2.47 (1H, m), 2.09-2.26 (2H, m),1.29 (3H, d). m/z [M+H]⁺ 298.

(R)-Phenyl{(2S)-4-[(1R)-1-phenylethyl]morpholin-2-yl}methylmethanesulphonate (51)

To a solution of 50 (0.05 g, 0.17 mmol) in dichloromethane (1 ml) atroom temperature was added polymer supported Hünig's base ((Argonaut,3.56 mmol/g, 0.089 g, 0.32 mmol, 1.9 eq) and methanesulphonyl chloride(0.02 g, 0.19 mmol). The mixture was stirred under nitrogen for 6 hoursthen filtered and concentrated in vacuo. The crude product was purifiedby flash column chromatography (eluent: ethyl acetate/heptane 33/67(v/v)) to give 51 as a colourless oil (0.035 g, 55%%); MW 375.49;C₂₀H₂₅NO₄S ¹H NMR (CDCl₃) 7.20-7.35 (10H, m), 5.46 (1H, d), 3.79-3.88(2H, m), 3.59 (1H,td), 3.4 (1H, q), 2.68-2.78 (2H, m), 2.68 (3H, s),2.03-2.24 (2H, m), 1.34 (3H, d). m/z [M+H]⁺ 376.

(2S)-4-[(1R)-1-Phenylethyl]-2-((S)-phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(52)

A mixture of 51 (0.035 g, 0.093 mmol), potassium carbonate (0.026 g,0.19 mmol) and 2-trifluoromethylbenzenethiol (0.084 g, 0.47 mmol) indry, degassed dimethylformamide (0.5 ml) was stirred under nitrogen atroom temperature for 3 days. The reaction mixture was diluted with waterand extracted with diethyl ether. The extracts was washed with water andbrine, dried over magnesium sulphate, filtered and evaporated to give acolourless oil (0.03 g, 71%). Purification by flash columnchromatography (eluent: ethyl acetate/heptane 20/80 [v/v]) gave 52 as acolourless oil (0.03 g, 71%); MW 457.56; C₂₆H₂₆F₃NOS ¹H NMR (CDCl₃) 7.53(1H, d), 7.10-7.28 (13H, m), 4.39 (1H, d), 3.85-4.04 (2H, m), 3.8 (1H,td), 3.35 (1H, q), 2.70 (1H, d), 2.40 (1H, d), 2.30 (1H, td), 2.10-2.20(1H, m), 1.29 (3H, d). m/z [M+H]⁺ 458.

Example 1 (2S)-2-((S)-Phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine (9) (S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl2-trifluoromethyl)phenyl sulfide (8)

Compound 8 was obtained from 5a (4.00 g, 11.55 mmol), 2-trifluoromethylthiophenol (2.47 g, 13.86 mmol, 1.2 eq) and caesium carbonate (4.95 g,15.24 mmol, 1.1 eq) in dimethylformamide (60 ml) as a brown oilfollowing a modification of General Procedure 1 in which the reactionwas carried out over 1 hour (6.04 g). The oil was purified by flashcolumn chromatography (eluent: hexane/ethyl acetate gradient 100 to90/10 [v/v]) to give a yellow oil (4.83 g, 94%); MW 443.54; C₂₅H₂₄F₃NOS;¹H NMR (CDCl₃): 7.60 (1H, dd, 7 Hz, 1 Hz), 7.17-7.39 (13H, m), 4.50 (1H,d, 7 Hz), 3.97-4.12 (2H, m), 3.73 (1H, dt, 10 Hz, 2 Hz), 3.59 (1H, d, 13Hz), 3.37 (1H, d, 13 Hz), 2.57-2.68 (2H, m); 2.18-2.38 (2H, m); LCMS(2.5 minute method): m/z 445 [M+H]+ @ Rt 1.50 min.

(2S)-2-((S)-Phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine (9)

Compound 9 (Example 1) was obtained from 8 (5.25 g, 11.84 mmol), solidsupported Hünig's base (Argonaut, 3.56 mmol/g, 6.64 g, 23.67 mmol, 2 eq)and α-chloroethyl chloroformate (3.83 ml, 35.51 mmol, 3 eq) in anhydrousdichloromethane (75 ml) following General Procedure 2a. Afterevaporation of solvents a light brown solid (5.60 g) was obtained whichwas recrystailised from iso-propanol. The solid was suspended in ethylacetate and washed with an aqueous solution of sodium hydroxide (50 mlof a 1M solution). The organic layer was washed with brine, dried overmagnesium sulphate and concentrated in vacuo to yield the free amine asa colourless oil (3.10 g, 74%); MW 353.41; C₁₈H₁₈F₃NOS; ¹H NMR (CDCl₃):7.46 (1H, d, 8 Hz), 7.24 (1H, d, 7 Hz), 7.05-7.2 (7H, m), 4.28 (1H, d, 8Hz), 3.92 (1H, d, 11 Hz), 3.80 (1H, q, 7 Hz), 3.58 (1H, dt, 2 Hz and 11Hz), 2.69-2.87 (2H, m), 2.59 (2H, d, 6 Hz), 2.13-1.90 (1H, br s); LCMS(10 minute method): m/z 354 [M+H]+ @ Rt 5.26 min. The hydrochloride saltof 9 was obtained following General Procedure 3.

An alternative method for the preparation of compound 9 (Example 1),according to Scheme 6, is as follows:

To a suspension of polymer supported Hünig's base (0.11 g, 0.40 mmol)and 52 (0.03 g, 0.066 mmol) in dry dichloromethane (1 ml) was addedα-chloroethyl chloroformate (0.09 g, 0.066 mmol) at room temperatureunder nitrogen. The mixture was stirred at room temperature over theweekend then filtered and concentrated in vacuo. This was taken up inmethanol, heated at 70° C. for 2 hours, cooled, and purified by SCXchromatography (eluent: ammonia/methanol 1/1 [v/v]) to give 9 as acolourless oil (0.01 g, 43%). The spectroscopic data for 9 obtained bythe route outlined here was identical to the data for 9 obtained asdescribed above.

Example 2 (2S)-2-((S)-Phenyl{[2-(thiomethyl)phenyl]thio}methyl)morpholine (11)(2S)-2-[(S)-{[2-(methylthio)phenyl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(10)

Compound 10 was obtained from 5a (4.0 g, 11.55 mmol),2-methylsulphenyl-thiophenol (2.17 g, 13.86 mmol, 1.2 eq) and caesiumcarbonate (4.42 g, 13.63 mmol, 1.18 eq) in dimethylformamide (35 ml)following a modification of General Procedure 1 in which the mixture washeated at 50° C. for 1.5 hours, allowed to cool to room temperature,taken up in methanol and treated with SCX-2 (100 g). The SCX-2 waswashed with methanol. 10 was obtained as a white solid (4.92 g) afterSCX chromatography (eluent: ammonia/methanol 1/1 [v/v]) and removal ofsolvents in vacuo. Purification by flash column chromatography (eluent:ethyl acetate/isohexane gradient 10/90 to 30/70 [v/v]) gave 10 as awhite solid (4.04 g, 83%); MW 421.63; C₂₇H₂₇NOS₂; ¹H NMR (CDCl₃):7.03-7.15 (6H, m), 6.93-6.99 (2H, m), 6.74 (1H, td, 7 Hz, 1 Hz), 4.31(1H, d, 8 Hz), 3.95 (1H, br, d, 12 Hz), 3.83 (1H, td, 8 Hz, 3.8 Hz),3.59 (1H, td, 11 Hz and 3 Hz), 2.82 (1H, td, 12 Hz and Hz), 2.61-2.75(3H, m), 2.35 (3H, s), 1.73 (1H, br, s); LCMS (6 minute method): m/z 422[M+H]+ @ Rt 3.36 min.

(2S)-2-((S)-Phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(11)

Compound 11 (Example 2) was obtained from 10 (4.02 g, 9.53 mmol), solidsupported Hünig's base (Argonaut, 3.56 mmol/g, 5.02 g, 17.87 mmol, 2 eq)and α-chloroethyl chloroformate (3.09 ml, 28.6 mmol, 3 eq) in anhydrousdichloromethane (75 ml) following General Procedure 2a. The mixture washeated at 40°C. for 1.5 hours then left to stir at room temperatureovernight. The reaction mixture was filtered and concentrated in vacuoto give a pale orange liquid. This was taken up in methanol (70 ml) andheated at 40° C. for 2 hours. A white solid crashed out of the solutionwhich was taken up in methanol and purified by SCX chromatography(eluent: ammonia/methanol 1/1 [v/v]). After evaporation in vacuo 11 wasobtained as a pale yellow oil (3.13 g, 99%); MW 331.50; C₁₈H₂₁NOS₂; ¹HNMR (CDCl₃): 7.03-7.15 (6H, m), 6.93-6.99 (2H, m), 6.74 (1H, td, 7 Hz, 2Hz), 4.31 (1H, d, 8 Hz), 3.95 (1H, br, d, 12 Hz), 3.83 (1H, td, 8 Hz, 4Hz), 3.59 (1H, td, 11 Hz, 3 Hz), 2.82 (1H, td, 12 Hz, 3 Hz), 2.61-2.75(3H, m), 2.35 (3H, s), 1.73 (1H, br, s). Compound 11 was converted intoits hydrochloride salt following a modification of General Procedure 3in which the pale yellow oil was taken up in isopropanol (˜200 ml) andfiltered. Addition of hydrogen chloride (19 ml of a 1M solution indiethyl ether, 19 mmol) gave a white precipitate to which furtherdiethyl ether (˜50 ml) was added. The solid was isolated by filtrationand washed with diethyl ether to give the hydrochloride salt of 11 as awhite solid (3.03 g, 78%); MW 367.96; C₁₈H₂₂ClNOS₂; ¹H NMR (CDCl₃): 9.94(211, br, s), 7.06-7.18 (6H, m), 6.94-7.03 (2H, m), 6.78 (1H, t, 7 Hz),4.24-4.32 (1H, m), 4.20 (1H, d, 6 Hz), 3.89-4.06 (2H, m), 3.18 (2H, br,t, 12 Hz), 2.99 (2H, br, s), 2.37 (3H, s); LCMS (10 minute method): m/z332 [M−HCl]+ @ Rt 5.07 min.

Example 3(2S)-2-[(S)-{[2-(1-methylethyl)phenyl]thiol}(phenyl)methylmorpholine(13)(2S)-2-[(S)-{[2-(1-methylethyl)phenyl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(12)

Compound 12 was obtained from 5a (4.04 g, 11.66 mmol),2-isopropylsulphenyl-thiophenol (2.35 ml, 14 mmol, 1.2 eq) and caesiumcarbonate (4.56 g, 14 mmol, 1.2 eq) in dimethylformamide (35 ml)following a modification of General Procedure 1 in which the mixture washeated at 90° C. for 20 minutes, allowed to cool to room temperature,taken up in ethyl acetate (50 ml), washed with water and brine, driedover sodium sulphate, filtered and reduced in vacuo to give a yellow oilwhich was purified by SCX chromatography (eluent: ammonia/methanol 1/1[v/v]). Removal of solvents in vacuo gave 12 as a white solid (4.45,91%); MW 417.62; C₂₇H₃₁NOS; ¹H NMR (CDCl₃): 7.14-7.26 (7H, m), 7.03-7.1(6H, m), 6.86-6.92 (1H, m), 4.10 (111, d, 8 Hz), 3.88-3.94 (2H, m), 3.62(1H, td, 11 Hz, 2 Hz), 3.37-3.47 (2H, m), 3.22 (1H, d, 13 Hz), 2.50 (2H,d, 11 Hz), 2.12-2.29 (2H, m), 1.05 (3H, d, 7 Hz), 0.92 (3H, d, 7 Hz);LCMS (6 minute method): m/z 418 [M+H]+ @ Rt 3.72 min.

(2S)-2-[(S)-{[2-(1-methylethyl)phenyl]thio}(phenyl)methyl]morpholine(13)

Compound 13 (Example 3) was obtained from 12 (4.44 g, 10.65 mmol), solidsupported Hünig's base (Argonaut, 3.56 mmol/g, 6.05 g, 21.54 mmol, 2 eq)and α-chloroethyl chloroformate (3.30 ml, 32.0 mmol, 3 eq) in anhydrousdichloromethane (50 ml) following General Procedure 2a. The mixture washeated at 40° C. for 1.5 hours then left to stir at room temperatureovernight. The reaction mixture was filtered and concentrated in vacuoto give a pale yellow liquid. This was taken up in methanol (50 ml) andheated at 60° C. for 1.5 hours. The reaction mixture was allowed to coolto room temperature and purified by SCX chromatography (eluent:ammonia/methanol 1/1 [v/v]) to give 13 as a pale yellow oil; MW 327.49;C₂₀H₂₅NOS; ¹H NMR (CDCl₃): 7.22 (1H, d, 8 Hz), 7.03-7.13 (7H, m),6.87-6.92 (1H, m), 4.04 (1H, d, 8 Hz), 3.94-3.99 (1H, m), 3.79 (1H, td,9 Hz, 3 Hz), 3.61 (1H, td, 11 Hz, 3 Hz), 3.41 (1H, sept., 7 Hz), 2.82(1H, td, 12 Hz and 3 Hz), 2.72 (1H, br, d, 12 Hz), 2.52-2.63 (2H, m),1.70 (1H, br, s), 1.05 (3H, d, 7 Hz), 0.91 (3H, d, 7 Hz). Compound 13was converted into its hydrochloride salt following a modification ofGeneral Procedure 3 in which the pale yellow oil was taken up in ether(50 ml), and filtered. Addition of hydrogen chloride in dry diethylether (19 ml of a 1M solution in diethyl ether) gave a white precipitateto which further diethyl ether (50 ml) was added. The reaction mixturewas concentrated and the residue washed with diethyl ether to give awhite solid (2.76 g, 69% overall yield from 5a); MW 363.95;C₂₀H₂₅NOS.HCl; ¹H NMR (CDCl₃): 9.91 (2H, br, s), 7.05-7.22 (7H, m),6.91-6.96 (2H, m), 4.23-4.31 (1H, m), 4.08-3.90 (3H, m), 3.31-3.41 (1H,m), 3.04-3.21 (2H, br, m), 2.91-2.99 (2H, br, m), 1.06 (3H, d, 7 Hz),0.93 (3H, d, 7 Hz); LCMS (10 minute method): m/z 327 [M−HCl]+ @ Rt 5.7min.

Example 4(2S)-2-[(S)-([1,1′-Biphenyl]-2-ylthio)(phenyl)methyl]morpholine (15)(2S)-2-[(S)-([1,1′-Biphenyl]-2-ylthio)(phenyl)methyl]-4-(phenylmethyl)morpholine(14)

Compound 14 was obtained from 5a (2.16 g, 6.24 mmol),2-phenylsulphenyl-thiophenol (2.35 ml, 14 mmol, 1.2 eq) and caesiumcarbonate (2.43 g, 7.5 mmol, 1.2 eq) in dimethylformamide (50 ml)following a modification of General Procedure 1 in which the mixture washeated at 90° C. for 20 minutes, allowed to cool to room temperature,taken up in ethyl acetate (50 ml), washed with water and brine, driedover sodium sulphate, filtered and reduced in vacuo to give a yellowoil. Purification by SCX-chromatography (eluent: ammonia/methanol 1/1[v/v]) followed by evaporation in vacuo gave 14 as a white solid (0.59g, 90%); MW 451.64; C₃₀H₂₉NOS; ¹H NMR (CDCl₃): 6.93-7.34 (19H, m), 3.92(1H, br, d, 6 Hz), 3.63-3.76 (2H, m), 3.45 (1H, t, 10 Hz), 3.33 (1H, d,13 Hz), 3.17 (1H, d, 12 Hz), 2.39 (1H, d, 12 Hz), 2.20 (1H, d, 11 Hz),1.97-2.07 (1H, m), 1.82-1.92 (1H, m); LCMS (6 minute method): m/z 452[M+H]+ @ Rt 3.69 min.

(2S)-2-[(S)-([1,1′-Biphenyl]-2-ylthio)(phenyl)methyl]morpholine (15)

Compound 15 (Example 4) was obtained from 14 (2.95 g, 6.54 mmol), solidsupported Hünig's base (Argonaut, 3.56 mmol/g, 13.06 g, 21.54 mmol, 2eq) and α-chloroethyl chloroformate (2.0 ml, 19.6 mmol, 3 eq) inanhydrous dichloromethane (50 ml) following General Procedure 2a. Thereaction mixture was concentrated in vacuo to give a pale yellow liquid.This was taken up in methanol (70 ml) and heated at 40° C. for 2 hours.A white solid crashed out of the solution which was taken up in methanoland purified by SCX-chromatography (eluent: ammonia/methanol 1/1 [v/v]).After removal of solvents in vacuo 15 was obtained as a pale yellow oil;MW 361.51; C₂₃H₂₃NOS; ¹H NMR (CDCl₃): 7.0-7.45 (14H, m), 3.95 (1H, d, 8Hz), 3.65-3.85 (2H, m), 3.35 (1H, d, 12 Hz), 3.2 (1H, d, 12 Hz), 2.45(1H, d, 10 Hz), 2.20 (1H, d, 10 Hz), 2.0-2.15 (1H, m), 1.8-2.0 (1H, m);LCMS (12 minute method): m/z 363 [M+H]+ @ Rt 3.00 min. 15 was convertedinto its hydrochloride salt following a modification of GeneralProcedure 3 in which the pale yellow oil was taken up in isopropanol(−200 ml), and filtered. Addition of hydrogen chloride (19 ml of a 1Msolution in diethyl ether) gave a white precipitate to which furtherdiethyl ether (˜50 ml) was added. The solid was isolated by filtrationand washed with diethyl ether to give the hydrochloride salt of 15 as awhite solid (1.95 g, 75% overall yield from 5a); MW 397.97;C₂₃H₂₃NOS.HCl; ¹H NMR (CDCl₃): 9.80 (2H, br, s), 7.38-7.03 (12H, m),6.90-6.96 (2H, m), 3.85-4.00 (2H, m), 3.72-3.82 (1H, m), 3.66 (1H, d, 5Hz), 2.98-3.10 (1H, m), 2.81 (1H, br, s), 2.62 (2H, br, s); LCMS (12minute method): m/z 362 [M+H]+ @ Rt 2.99 min.

Example 5 (2S)-2-[(S)-[(2-Fluorophenyl)thio](phenyl)methyl]morpholine(17)(2S)-2-[(S)-[(2-Fluorophenyl)thio](phenyl)methyl]4-phenylmethyl)morpholine(16a) and(2R)-2-[(R)-[(2-Fluorophenyl)thio](phenyl)methyl]-4-phenylmethyl)morpholine(16b)

Compounds 16a,16b were obtained from 5a,5b (0.114 g, 0.33 mmol),2-fluorothiophenol (0.045 g, 0.36 mmol, 1.2 eq) and caesium carbonate(0.12 g, 0.36 mmol, 1.2 eq) in dimethylformamide (50 ml) followingGeneral Procedure 1 as a pale yellow oil (0.14 g, 65%); MW 393.53;C₂₄H₂₄FNOS; ¹H NMR (CDCl₃): 7.12-7.36 (12H, m), 6.87-6.99 (2H, m), 4.48(1H, d, 8 Hz), 4.00-4.11 (2H, m), 3.77 (1H, td, 11 Hz, 2 Hz), 3.60 (1H,d, 13 Hz), 3.37 (1H, d, 13 Hz); 2.63 (2H, t, 10 Hz), 2.16-2.31 (2H, m);LCMS (2.5 minute method): m/z 394 [M+H]+ @ R_(t) 1.41 min.

(2S)-2-[(S)-[(2-Fluorophenyl)thio](phenyl)methyl]morpholine (17)

Compound 17 (Example 5) was obtained from 16a,16b (0.72 g, 0.18 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 2.0 g, 0.56 mmol, 3eq) and α-chloroethyl chloroformate (0.62 ml, 0.56 mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as aviscous yellow oil (0.046 g, 82%) from which 17 was obtained as a singleisomer after separation by chiral HPLC (0.016 g); Chiral LC (AD): 10.83min. LC purity=91% (UV254 nm)/98% (ELS); LCMS (10 minute method): m/z304 [M+H]+ @ Rt 5.82 min; HPLC purity=84% (UV215 nm)/98% (ELS); MW303.41; C₁₇H₁₈FNOS; ¹H NMR (CDCl₃): 7.13-7.00 (7H, m), 6.87-6.76 (2H,m), 4.29 (1H, d, 9 Hz), 3.98-3.93, (1H, m), 3.78 (1H, td, 9 Hz and 4Hz), 3.60 (1H, td, 11 Hz and 3 Hz), 2.82 (1H, td, 12 Hz, 3 Hz),2.76-2.70 (1H, m), 2.57-2.53, (2H, m), NH signal not observed; LCMS (10minute method): m/z 304 [M+H]+ @ Rt 5.84 min; HPLC purity=100%% (BLS).Compound 17 was converted into its hydrochloride salt following GeneralProcedure 3.

Example 6 (2S)-2-[(S)-[(2-Ethylphenyl)thio](phenyl)methyl]morpholine(19)(2S)-2-[(S)-[(2-Ethylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(18a) and(2R)-2-[(R)-[(2-Ethylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(18b)

Compounds 18a,18b were obtained from 5a,5b (0.2 g, 0.58 mmol),2-ethyl-thiophenol (0.16 g, 1.16 mmol, 2 eq) and caesium carbonate (0.23g, 0.7 mmol, 1.2 eq) in dimethylformamide (5 ml) following modificationof General Procedure 1 in which the reaction mixture was heated to 95°C. for 2 hours. After purification by flash column chromatography(eluent: ethyl acetate/hexane 9/1 [v/v]) 18a,18b was obtained as a whitesolid (0.15 g, 65%%); MW 403.59; C₂₆H₂₉NOS; ¹H NMR (CDCl₃): 6.96-7.40(14H, m), 4.22 (1H, d, 7 Hz), 3.96-4.01 (2H, m), 3.72 (1H, td, 11 Hz and2 Hz), 3.52 (1H, d, 13 Hz), 3.32 (1H, d, 13 Hz), 2.68 (2H, q, 8 Hz),2.59 (2H, br d, 12 Hz), 2.06-2.21 (2H, m), 1.12 (3H, t, 7 Hz); LCMS (2.5minute method) m/z 404 [M+H]+ @ Rt 1.49 min.

(2S)-2-[(S)-[(2-Ethylphenyl)thio](phenyl)methyl]morpholine (19)

Compound 19 (Example 6) was obtained from 18a,18b (0.18 g, 0.52 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 3.7 g, 1.04 mmol, 2eq) and α-chloroethyl chloroformate (0.34 ml, 3.12 mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as aviscous yellow oil (0.21 g, 86%) from which 19 was obtained afterseparation by chiral HPLC on chiral OD semi-preparative column; chiralLC (OD): 15.95 min. LC purity=100% (UV254 nm)/100% (LS); MW 313.47;C₁₉H₂₃NOS; ¹H NMR (CDCl₃): 7.17 (1H, d, 8 Hz), 7.12-7.05 (5H, m), 7.01(2H, d, 4 Hz), 6.87-6.93 (1H, m), 4.07 (1H, d, 8 Hz), 3.92-3.97 (1H, m),3.74-3.80 (1H, m), 3.59 (1H, td, 11 Hz, 3 Hz), 2.80 (1H, td, 12 Hz and 3Hz), 2.71 (1H, br, d, 12 Hz), 2.63-2.54 (4H, m), 1.64 (1H, br, s), 1.04(3H, t, 8 Hz); LCMS (10 minute method): m/z 314 [M+H]+ @ Rt 5.92 min. 19was converted into its hydrochloride salt following General Procedure 3;MW 349.93; C₁₉H₂₃NOS.HCl; ¹H NMR (CDCl₃): 10.10 (2H, br, s), 7.13-7.28(8H, m), 7.02-7.08 (1H, m), 4.36 (1H, br, s), 4.01-4.17 (3H, br, m),3.16-3.31 (2H, br, m), 2.92-3.09 (2H, br, m), 2.71 (2H, q, 8 Hz), 1.15(3H, t, 7 Hz).

Example 7(2S)-2-[(S)-{[2-(Methyloxy)phenyl]thio}(phenyl)methyl]morpholine (21)(2S)-2-[(S)-{[2-(Methyloxy)phenyl]thio}(henyl)methyl]-4-(phenylmethyl)morpholine(20a) and(2R)-2-[(R)-{[2-(Methyloxy)phenyl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(20b)

Compounds 20a,20b were obtained from 5a,5b (0.18 g, 0.52 mmol),2-methoxy thiophenol (0.074 ml, 0.57 mmol, 1.2 eq) and caesium carbonate(0.17 g, 0.52 mmol, 1.2 eq) in dimethylformamide (5 ml) followingmodification of General Procedure 1 in which the reaction was heated at95° C. for 2.5 hours. After purification by flash column chromatography(eluent: ethyl acetate/hexane gradient 15/85 to 25/75 [v/v]) 20a,20b wasobtained as a viscous yellow oil (0.17 g, 83%); MW 405.56; C₂₅H₂₇NO₂S;¹H NMR (CDCl₃): 7.01-7.26 (12H, m), 6.58-6.63 (2H, m), 4.39 (1H, d, 7Hz), 3.86-3.91 (2H, m), 3.71 (3H, s), 3.56-3.62 (1H, m), 3.42 (1H, d, 11Hz); 3.21 (1H, d, 11 Hz), 2.46-2.52 (2H, m), 2.01-2.11 (2H, m); LCMS (10minute method): m/z 406 [M+H]⁺ @ R_(T) 6.09 min.

(2S)-2-[(S)-{[2-(Methyloxy)phenyl]thio}(phenyl)methyl]morpholine (21)

Compound 21 (Example 7) was obtained from 20a,20b (0.1 g, 0.25 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 1.78 g, 0.5 mmol, 2eq) and α-chloroethyl chloroformate (0.16 ml, 1.5 mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as aviscous yellow oil (0.06 g, 77%) from which 21 was obtained afterseparation by chiral HPLC on a Chiralcel OJ semi-preparative column.Chiral LC: 11.45 min. LC purity=100%; MW 315.44; C₁₈H₂₁NO₂S; ¹H NMR(CDCl₃): 7.14-7.34 (7H, m), 6.74-6.84 (2H, m), 4.50 (1H, d, 8 Hz), 4.10(1H, d, 11 Hz), 3.85-4.00 (4H, m), 3.74 (1H, dt, 1 Hz, 11 Hz), 2.82-3.02(2H, m), 2.66-3.02 (3H, m); LCMS (10 minute method): m/z 316 [M+H]⁺ @R_(t) 4.87 min. 21 was converted its hydrochloride salt followingGeneral Procedure 3.

Example 8(2S)-2-[(S)-({2-[(1-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]morpholine(23)(2S)-2-[(S)-({2-[(1-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]-4-(phenylmethyl)morpholine(22a) and(2R)-2-[(R)-({2-[(1-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]-4-(phenylmethyl)morpholine(22b)

Compounds 22a,22b were obtained from 5a,5b (0.57 g, 1.7 mmol),2-isopropoxy-thiophenol (0.94 g, 5.61 mmol) and caesium carbonate (2.18g, 6.72 mmol, 1.2 eq) in dimethylformamide (15 ml) followingmodification of General Procedure 1 in which the reaction mixture washeated to 95° C. for 3 hours. After purification by SCX chromatography(eluent: ammonia/methanol 1/1 [v/v]) 22a,22b was obtained as a darkyellow oil (0.56 g, 76%%); MW 433.62; C₂₇H₃₁NO₂S; ¹H NMR (CDCl₃):7.01-7.24 (7H, m), 6.94-7.09 (5H, m), 6.64 (1H, d, 8 Hz), 6.56 (1H, td,8 Hz, 1 Hz), 4.42-4.51 (2H, m), 3.83-3.92 (2H, m), 3.56 (1H, td, 11 Hzand 3 Hz), 3.42 (1H, d, 13 Hz), 3.24 (1H, d, 13 Hz), 2.52 (1H, d, 11Hz), 2.46 (1H, d, 11 Hz), 2.05-2.17 (2H, m), 1.29 (3H, d, 6 Hz), 1.27(3H, d, 6 Hz); LCMS (2.5 minute method): m/z 434 [M+H]⁺ @ R_(T) 1.44min.

(2S)-2-[(S)-({2-[(1-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]morpholine(23)

Compound 23 (Example 8) was obtained from 22a,22b (0.56 g, 1.3 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.73 g, 2.6 mmol, 2eq) and α-chloroethyl chloroformate (0.16 ml, 1.5 mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as aviscous yellow oil (0.41 g, 93%) after separation using chiral HPLC on aOD semi-preparative column. Chiral LC (OD): 12.51 min. LC purity=100%(UV254 nm)/100% (ELS); MW 343.49; C₂₀H₂₅NO₂S; ¹H NMR (CDCl₃): 7.13-7.20(1H, m), 6.96-7.12 (6H, m), 6.67 (1H, d, 8 Hz), 6.59 (1H, td, 7 Hz, 1Hz), 4.48 (1H, sept., 6 Hz), 4.38 (1H, d, 7 Hz), 3.90-3.95 (1H, m), 3.73(1H, td, 8 Hz, 4 Hz), 3.54 (1H, td, 11 Hz and 3 Hz), 2.79 (1H, td, 12 Hzand 3 Hz), 2.62-2.72 (3H, m), 1.55 (1H, br, s), 1.32 (3H, d, 6 Hz), 1.29(3H, d, 6 Hz); LCMS (10 minute method): m/z 344 [M+H]+ @ Rt 6.19 min;HPLC purity=92% (UV215 nm). 23 was converted into its hydrochloride saltfollowing General Procedure 3; MW 379.95; C₂₀H₂₅NO₂S.HCl; ¹H NMR(CDCl₃): 9.81-10.04 (2H, br, m), 7.03-7.25 (7H, m), 6.71 (1H, d, 8 Hz),6.63 (1H, t, 7 Hz), 4.51 (1H, sept., 6 Hz), 4.31 (1H, d, 6 Hz),4.15-4.23 (1H, m), 3.83-4.03 (2H, m), 3.05-3.18 (2H, m), 2.80-3.03 (2H,m), 1.31 (3H, d, 6 Hz), 1.29 (3H, d, 6 Hz).

Example 9 2-{[(S)-(2S)-Morpholin-2-yl(phenyl)methyl]thio}phenyltrifluoromethyl ether (25)(2S)-4-(Phenylmethyl)-2-[(S)-phenyl({2-[(trifluoromethyl)oxy]phenyl}thio)methyl]morpholine(24a) and(2S)-4-(Phenylmethyl)-2-[(S)-phenyl({2-[(trifluoromethyl)oxy]phenyl}thio)methyl]morpholine(24b)

Compounds 24a,24b were obtained from 5a,5b (0.011 g, 0.33 mmol),2-trifluoromethoxythiophenol (1.2 eq, 0.077 g, 0.39 mmol) and caesiumcarbonate (0.15 g, 0.47 mmol, 1.2 eq) in dimethylformamide (15 n−1)following modification of General Procedure 1 in which the reaction washeated at 95° C. for 1.5 hours. The reaction mixture was allowed to coolto room temperature, diluted with ethyl acetate (20 ml), washedsequentially with water and brine, dried over sodium sulphate andfinally concentrated in vacuo to give a pale yellow oil (0.14 g, 92%);MW 459.53; C₂₅H₂₄F₃NO₂S; ¹H NMR (CDCl₃): 7.13-7.41 (13H, m), 7.08-7.13(1H, m), 4.51 (1H, d, 8 Hz), 3.99-4.07 (2H, m), 3.73 (1H, td, 9 Hz, 2.5Hz), 3.57 (1H, d, 13 Hz), 3.37 (1H, d, 13 Hz); 2.57-2.66 (2H, m),2.20-2.31 (2H, m); LCMS (10 minute method): m/z 460 [M+H]⁺ @ R_(t) 6.69min.

2-{[(S)-(2S)-Morpholin-2-yl(phenyl)methyl]thio}phenyl trifluoromethylether (25)

Compound 25 (Example 9) was obtained from 24a,24b (0.06 g, 0.13 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.073 g, 0.026mmol, 2 eq) and α-chloroethyl chloroformate (0.04 ml, 0.39 mmol, 3 eq)in anhydrous dichloromethane (5 ml) following General Procedure 2a as aviscous yellow oil (0.021 g, 44%) from which 25 was obtained afterseparation using chiral HPLC on a OD semi-preparative column. Chiral LC(03): 12.60 min. LC purity=98% (UV_(254 nm))/100% (ELS); MW 369.41;C₁₈H₁₈F₃NO₂S; ¹H NMR (CDCl₃): 7.02-7.21 (8H, m), 6.91-6.96 (1H, m), 4.28(1H, d, 8 Hz), 3.93 (1H, br, d 11 Hz), 3.75-3.81 (1H, m), 3.60 (1H, td,11 Hz and 3 Hz), 2.71-2.86 (2H, m), 2.61 (2H, d, 6 Hz), 1.90 (1H br, s);LCMS (10 minute method): m/z 370 [M+H]⁺ @ R_(t) 5.86 min.

Example 10 (2S)-2-[(S)-[(2-Methylphenyl)thio](phenyl)methyl]morpholine(27) (2S)-2-[(S)-[(2-Methylphenyl)thio](phenyl)methyl]-4(phenylmethyl)morpholine (26a) and(2R)-2-[(R)-[(2-Methylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(26b)

Compounds 26a,26b were obtained from 5a,5b (0.1 g, 0.29 mmol), 2-methylthiophenol (0.04 ml, 0.31 mmol) and caesium carbonate (0.125 g, 0.37mmol, 1.2 eq) in dimethylformamide (15 ml) following General Procedure 1as a colourless oil (0.13 g, 85%); MW 389.56; C₂₅H₂₇NOS; ¹H NMR (CDCl₃):6.84-7.24 (14H, m), 4.14 (1H, d, 8 Hz), 3.85-3.95 (2H, m), 3.60 (1H, dt,10 Hz, 3 Hz), 3.42 (1H, d, 13 Hz); 3.21 (1H, d, 13 Hz), 2.46-2.54 (2H,m), 2.18 (3H, s), 1.97-2.13 (2H, m); LCMS (2.5 minute method): m/z 390[M+H]⁺ @ R_(T) 1.49 min.

(2S)-2-[(S)-[(2-Methylphenyl)thio](phenyl)methyl]morpholine (27)

Compound 27 (Example 10) was obtained from 26a,26b (0.04 g, 0.12 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.89 g, 0.24 mmol,2 eq) and α-chloroethyl chloroformate (0.04 ml, 0.36 mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as aviscous yellow oil (0.03 g, 75%) from which 27 was obtained after chiralseparation. Chiral LC (OJ): 15.84 min. LC purity=98.57% (UV_(254 nm));MW 299.44; C₁₈H₂₁NOS; ¹H NMR (CDCl₃): 6.86-7.21 (9H, m), 4.08 (1H, d, 7Hz), 3.75 (1H, br s), 3.58 (1H, br s), 2.34-3.1 (4H, m), 2.20 (3H, s);1.41-2.04 (2H, m); LCMS (10 minute method): m/z 300 [M+H]⁺ @ R_(T) 5.08min. 27 was converted into its hydrochloride salt following GeneralProcedure 3.

Example 11 (2S)-2-{(S)-Phenyl[(2-propylphenyl)thio]methyl}morpholine(29)(S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl-2-propylphenylsulfide (28a) and

Compounds 28a,28b were obtained from 5a (0.53 g, 1.50 mmol), 2-n-propylthiophenol (0.025 g, 1.65 mmol) and caesium carbonate (0.59 g, 1.8 mmol,1.2 eq) in dimethylformamide (5 ml) following a modification of GeneralProcedure 1 in which the reaction was heated at 95° C. for 3 hours.After purification by SCX column chromatography (eluent:ammonia/methanol 1/1 [v/v]) 28a,28b was obtained as a dark yellow oil(0.56 g, 90%%); MW 417.62; C₂₇H₃₁NOS; ¹H NMR (CDCl₃): 7.23-7.12 (6H, m),7.06-7.11 (5H, m), 6.97-6.99 (2H, m), 6.87-6.92 (1H, m), 4.13 (1H, d, 8Hz), 3.86-3.94 (2H, m), 3.61 (1H, td, 11 Hz, 2 Hz), 3.44 (1H, d, 13 Hz),3.23 (1H, d, 13 Hz), 2.46-2.59 (4H, m), 2.01-2.14 (2H, m), 1.34-1.52(2H, m), 0.83 (3H, t, 7 Hz); LCMS (2.5 minute method): m/z 418 [M+H]⁺ @R_(t) 1.55 min.

(2S)-2-{(S)-Phenyl[(2-propylphenyl)thio]methyl}morpholine (29)

Compound 29 (Example 11) was obtained from 28a,28b (0.56 g, 1.35 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.75 g, 2.7 mmol, 2eq) and α-chloroethyl chloroformate (0.44 ml, 4.05 mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as aviscous yellow oil (0.41 g, 93%); MW 327.49; C₂₀H₂₅NOS; ¹H NMR (CDCl₃):7.17 (1H, br, d, 7 Hz), 7.07-7.12 (5H, m), 6.96-7.00 (2H, m), 6.88-6.93(1H, m), 4.07 (1H, d, 8 Hz), 3.93-3.98 (1H, m), 3.74-3.80 (1H, m), 3.60(1H, td, 11 Hz, 3 Hz), 2.81 (1H, td, 12 Hz and 3 Hz), 2.72 (1H, br, d,12 Hz), 2.48-2.62 (4H, m), 1.36-1.59 (3H, m), 0.83 (3H, t, 7 Hz); LCMS(2.5 minute method): m/z 328 [M+H]⁺ @ R_(t) 1.40 min (single majorpeak).

Example 12 Methyl2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}benzoate (31)Methyl-2-({(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)benzoate(30a) andMethyl-2-({(R)-phenyl[(2R)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)benzoate(30b)

Compounds 30a,30b were obtained from 5a,5b (0.5 g, 1.45 mmol), methylthiosalicylate (0.49 g, 2.89 mmol) and potassium carbonate (0.21 g, 1.52mmol) in dry tetrahydrofurane (5 ml) following modification of GeneralProcedure 1 in which the solvents were degassed and purged with nitrogenbefore the addition of methyl thiosalicylate. The reaction mixture wasstirred at room temperature for 18 hours after which time the reactionmixture was poured onto water and extracted twice with diethyl ether.The organic layers were washed with water, dried and evaporated invacuo. After purification by SCX column chromatography (eluent:ammonia/methanol 1/1 [v/v]) 30a,30b was obtained as a colourless solid(0.18 g, 29%%); MW 433.57; C₂₆H₂₇NO₃S; ¹H NMR (CDCl₃): 8.65-8.85 (1H,m), 6.95-7.45 (13H, m), 4.45 (1H, d, 8 Hz), 3.85-4.05 (1H, m), 3.8 (3H,s), 3.65 (1H, dt, 1 Hz and 7 Hz), 3.55 (1H, d, 11 Hz), 3.25 (1H, d, 11Hz), 2.5-2.6 (2H, m); 2.0-2.15 (2H, m); FIA: m/z 462 [M+H]⁺.

Methyl 2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}benzoate (31)

Compound 31 (Example 12) was obtained from 30a,30b (0.2 g, 0.46 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.08 g, 2.77 mmol,6 eq) and α-chloroethyl chloroformate (0.5 ml, 4.62 mmol, 10 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as awhite solid (0.16 g, 91%) from which 31 was obtained after separationusing chiral HPLC on chiral OJ semi-preparative column. Chiral LC (OJ):12.32 min. LC purity=100% (UV_(254 nm)); MW 343.45. 31 was convertedinto its hydrochloride salt following General Procedure 3; ¹H NMR(d₆-DMSO): 9.30-9.5 (1H, m), 7.75-7.80 (1H, m), 7.1-7.55 (8H, m), 4.82(1H, d, 8 Hz), 3.95-4.15 (2H, m), 3.65.3.9 (3H, m), 3.55 (3H, s),2.80-3.25 (2H, m).

Example 13(2S)-2-((S)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morpholine (33)(2S)-2-((S)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(32a) and(2R)-2-((R)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(32b)

Compounds 32a,32b were obtained as outlined in Scheme 5 from 38a,38b(0.33 g, 0.91 mmol) following General Procedure 4 as a white solid aftercolumn chromatography (0.28 g, 67%); MW 461.53; C₂₅H₂₃F₄NOS; ¹H NMR(CDCl₃) 6.75-7.65 (1H, m), 6.85-7.33 (12H, m), 4.45 (2H, d, 8 Hz),3.6-3.75 (2H, m), 3.45 (1H, d 12 Hz), 3.3 (1H, d 12 Hz), 2.45-2.7 (2H,br, m),), 2.1-2.3 (2H, br, m); FIA: m/z 462 [M+H]⁺.

(2S)-2-((S)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(33)

Compound 33 (Example 13) was obtained from 32a,32b (0.28 g, 0.615 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.19 g, 0.68 mmol,1.1 eq) and α-chloroethyl chloroformate (0.07 ml, 0.68 mmol, 1.1 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as acolourless oil (0.22 g, 95%) from which 33 was obtained after chiralchromatography on a Chiralcel OJ semi-preparative column. Chiral LC(OJ): 13.33 min. LC purity=98.37% (UV_(254 nm)); MW 371.4; C₁₈H₁₇F₄NOS.LCMS (12 minute method): m/z 372 [M+H]+ @ Rt 5.2 min. 33 was convertedinto its hydrochloride salt following General Procedure 3; MW 407.86;C₁₈H₁₇F₄NOS.HCl; ¹H NMR (CDCl₃) 9.8-10.2 (1H, br), 7.4-7.6 (1H, m),(6.85-7.45 (8H, m), 4.05-4.45 (4H, br, m), 2.90-3.41 (4H, br, m).

Example 14(2S)-2-((S)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morpholine (35)(2S)-2-((S)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(34a) and(2R)-2-((R)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(34b)

Compounds 34a,34b were obtained as outlined in Scheme 5 from 39a,39b(0.4 g, 1.06 mmol, 1.1 eq), cesium carbonate (0.33 g, 1.0 mmol, 1.1 eq),and 2-trifluoromethyl benzene thiol (0.19 g, 1.06 mmol, 1.1 eq)following a modification of General Procedure 1 in which the reactionwas stirred at room temperature for 1.5 hours as a white solid aftercolumn chromatography (eluent: gradient hexane/ethyl acetate 10/90 to25/75[v/v]) (0.409 g, 80%); MW 477.98; C₂₅H₂₃F₃ClNOS, ¹H NMR (CDCl₃)7.1-7.65 (13H, m), 4.45 (1H, d, 8 Hz), 3.85-4.0 (2H, m), 3.55 (1H, m),3.3 (1H, d 12 Hz), 3.3 (1H, d 12 Hz), 2.45-2.65 (2H, br),), 2.1-2.3 (2H,br, m); FIA: m/z 478 [M+H]⁺.

(2S)-2-((S)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(35)

Compound 35 (Example 14) was obtained from 34a,34b (0.41 g, 0.86 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.27 g, 0.94 mmol,1.1 eq) and α-chloroethyl chloroformate (0.10 ml, 0.94 mmol, 1.1 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as acolourless oil (0.28 g, 84% yield) from which 35 was obtained afterseparation using chiral HPLC on a ChiralPak-AD OJ semi-preparativecolumn; MW 387.85; C₁₈H₁₇ClF₃NOS; LCMS (12 minute method): m/z 372[M+H]+ @ Rt 5.2 min. 35 was converted into its hydrochloride saltfollowing General Procedure 3; MW 423.96; C₁₈H₁₇ClF₃NOS.HCl; ¹H NMR(CDCl₃): 9.8-10.2 (1H, br), 7.4-7.6 (1H, m), 7.07-7.35 (7H, m), 3.84.45(4H, br, m), 2.85-3.45 (4H, br, m).

Example 15(2S)-2-((S)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)morpholine(37)(2S)-2-((S)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(36a) and(2R)-2-((R)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(36b)

Compounds 36a,36b were obtained from 7a,7b (0.45 g, 1.17 mmol), cesiumcarbonate (0.42 g, 1.29 mmol, 1.1 eq), and 2-methoxy-thiophenol (0.82 g,5.87 mmol) following a modification of General Procedure 1 in which thereaction mixture was heated to 95° C. for 2 hours and then stirred atroom temperature for 18 hours. After purification by flash columnchromatography (eluent: heptane/ethyl acetate 80/20 [v/v]) 18,18b wasobtained as a colourless oil (0.36 g, 72%%); MW 423.55; C₂₅H₂₆FNOS; ¹HNMR (CDCl₃): 6.65-7.5 (13H, m), 4.9 (1H, d, 7 Hz), 3.9-4.05 (2H, m), 3.8(3H, s), 3.6 (1H, dt, 8 Hz and 1 Hz), 3.45 (1H, d, 13 Hz), 3.15 (1H, d,13 Hz), 2.60 (2H, t, 8 Hz), 2.05-2.2 (2H, m); FIA: m/z 424 [M+H]⁺.

(2S)-2-((S)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)morpholine(37)

Compound 37 (Example 15) was obtained from 36a,36b (0.43 g, 1.02 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.37 g, 1.12 mmol,1.1 eq) and α-chloroethyl chloroformate (1.08 ml, 10.12 mmol, 10 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2a as acolourless oil (0.34 g, 99%) after separation by chiral HPLC on aChiralPak-AD semi-preparative column. Chiral LC: 12.86 min. LCpurity=99.1 (UV_(254 nm)); MW 369.89; C₁₈H₂₀FNOS; HA: m/z 334 [M+H]⁺. 37was converted into its hydrochloride salt following General Procedure 3;MW 333.43; C₁₈H₂₀FNOS; ¹H NMR (CDCl₃): 7.2-7.3 (1H, m), 6.85-7.2 (8H,m), 4.85 (1H, d, 8 Hz), 3.95-4.15 (2H, m), 3.85.3.9 (3H, m), 3.7 (1H,dt, 1 Hz and 7 Hz), 2.6-3.0 (4H, m).

Example 162-[2-Methyl-1-(2-trifluoromethyl-phenylsulfanyl)-propyl]-morpholine (56)4-Benzyl-2-(1-hydroxy-2-methyl-propyl)-morpholin-3-one (53)

To a stirred solution of 2 (5.05 g, 26.4 mmol) in tetrahydrofuran (25ml) at −78° C. under nitrogen was added lithium diisopropylamide (14.5ml of a 2M solution, 29.0 mmol) dropwise over 40 minutes. The reactionmixture was stirred at the same temperature over 30 minutes after whichtime a solution of isobutyraldehyde (2.63 ml, 29.0 mmol) intetrahydrofuran (15 ml) was added dropwise over 30 minutes. After onehour, the reaction mixture was allowed to warm to room temperature andquenched by addition of saturated ammonium chloride solution. Extractionwith dichloromethane and drying over magnesium sulphate gave 53 as amixture of diastereomers. Upon concentration in vacuo one diastereomerprecipitated as a white solid (53a: 0.99 g). The remaining motherliquors were purified by column chromatography (30% ethyl acetate inhexane [v/v]) to give 53 (2.06 g). MW 263.34; C₁₅H₂₁NO₃; LCMS (6 minmethod): m/z 286 [M+Na]⁺; RT=2.748.

1-(4-Benzyl-morpholin-2-yl)-2-methyl-propan-1-ol (54)

To a stirred solution of 53 (1.97 g, 7.47 mmol) in tetrahydrofuran (50ml) at room temperature under nitrogen was added borane-tetrahydrofurancomplex (30 ml of a 1M solution, ca 4 eq.). The reaction was heated to60° C. and followed by TLC-analysis. When all starting material had beenconsumed a few drops of methanol were added followed by a similar amountof 1N hydrochloric acid and heating was continued for another hour.Organic solvents were removed in vacuo and the remaining solution waspoured onto 1M potassium carbonate solution (30 ml), extracted withdiethyl ether. The organic layers were dried over magnesium sulphate andpurified by column chromatography (gradient from 15% ethyl acetate inhexane [v/v]) gave 54 (1.8 g, 97%). MW 249.36; C₁₅H₂₃NO₂; LCMS (6 minmethod): m/z 250 [M+H]⁺; RT=0.838.

4-Benzyl-2-[2-methyl-1-(2-trifluoromethyl-phenylsulfanyl)-propyl]-morpholine(55)

Compound 55 was obtained from 54 in a two-step procedure. To a stirredsolution of 54 (1.8 g, 7.2 mmol) in dichloromethane (50 ml) at roomtemperature was added solid solid supported Hünig's base (Argonaut, 3.56mmol/g, 6.2 g, 22 mmol, 3 eq) followed methanesulphonyl chloride (1.12ml, 14 mmol). After stirring for one hour, the reaction mixture wasfiltered and the filtrates washed with brine and dried over magnesiumsulphate to give the intermediate mesylate as a yellow oil (2.93 g ofisolated crude product). The crude product was taken up in drydimethylformamide (50 ml), 2-trifluoromethyl benzenethiol (2.1 ml, 14mmol) and solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.55 g,1.95 mmol) were added and the mixture heated to 70° C. and stirred for72 hours. The reaction was quenched by addition of water (50 ml) andsodium hydroxide solution (70 ml of a 2N solution). The aqueous layerwas extracted with diethyl ether (3×50 ml), washed with brine and driedover magnesium sulphate. Purification by ion-exchange chromatographyfollowed by preparative HPLC gave 55. MW 409.52; C₂₂H₂₆F₃NOS; LCMS (6min method): m/z 410 [M+H]⁺; RT=3.398.

2-[2-Methyl-1-(2-trifluoromethyl-phenylsulfanyl)-propyl]-morpholine (56)

Compound 56 (Example 16) was obtained from 55 (0.8 g, 1.95 mmol), solidsupported Hünig's base (Argonaut, 3.56 mmol/g, 1.65 g, 5.85 mmol, 3 eq)and α-chloroethyl chloroformate (0.4 ml, 3.9 mmol, 2 eq) in anhydrousdichloromethane (20 ml) following General Procedure 2a as a colourlessoil (0.5 g, 85% yield). Chiral HPLC on a ChiralCel-OD(3671) column using50% heptane in ethanol [v/v] gave 2 fractions (Rt=8.793 min and 10.443min). Conversion into fumarate salt 56 was carried out by dissolving indiethyl ether and addition of small amount of methanol. Data for 56derived from fraction with Rt=8.793 min: MW 435.46; C₁₉H₂₄F₃NO₅S; ¹H NMR(d₃-MeOD): 6.2-6.3 (2H, m), 6.1-6.2 (1H, m), 5.2 (1H, s), 2.6-2.7 (2H,m), 2.2-2.4 (1H, m), 1.6-1.9 (4H, m), 1.6-1.7 (1H, m), −0.4-−0.5 (6H,m).

Example 17 2-[2-Methyl-1-(2-trifluoromethyl-phenoxy)-propyl]-morpholine(58)4-Benzyl-2-[2-methyl-1-(2-trifluoromethyl-phenoxy)-propyl]-morpholine(57)

To a solution of 53a (0.146 g, 0.585 mmol) in dry dimethylformamide (2ml) under nitrogen and ice-cooling was added sodium hydride (26 mg of a60% dispersion in oil, 0.644 mmol) portionwise. The reaction was allowedto warm to room temperature for 30 minutes before addition of2-fluoro-benzotriflouride (0.07 ml, 0.66 mmol). After stirring for 12hours, another 0.5 equivalents of reagents were added and the reactionmixture heated to 40° C. for 30 minutes and then to 60° C. for another 2hours. The crude reaction mixture was purified by ion-exchange columnchromatography followed by preparative HPLC to give 57 (0.208 g, 92%yield) MW 393.45; C₂₂H₂₆F₃NO₂; LCMS (6 min method): m/z 394 [M+H]⁺;RT=3.150.

2-[2-Methyl-1-(2-trifluoromethyl-phenoxy)-propyl]-morpholine (58)

Compound 58 (Example 17) was obtained from 57 (0.21 g, 0.53 mmol), solidsupported Hünig's base (Argonaut, 3.56 mmol/g, 0.45 g, 1.5 mmol, 3 eq)and α-chloroethyl chloroformate (0.11 ml, 1.06 mmol, 2 eq) in anhydrousdichloromethane (10 ml) following General Procedure 2 as a colourlessoil (0.147 g, 92% yield) MW 303.33; C₁₅H₂₀F₃NO₂; ¹H NMR (CDCl₃): 7.5-7.6(1H, m), 7.2-7.4 (1H, m), 7.0-7.1 (1H, m), 6.8-6.95 (1H, m), 4.15-4.25(1H, m), 3.6-3.9 (2H, m), 3.4-3.6 (1H, m), 2.6-2.9 (4H, m), 2.15 (1H,br, s)1.8-2.1 (1H, m), 1.1-1.2 (6H, m); LCMS (12 min method): m/z 304[M+H]⁺; RT=4.862.

The pharmacological profile of the present compounds may be demonstratedas follows. All of the exemplified compounds above have been found toexhibit a K_(i) value less than 500 nM at the norepinephrine transporteras determined using the scintillation proximity assay described below.Furthermore, all of the exemplified compounds above have been found toselectively inhibit the norepinephrine transporter relative to theserotonin and dopamine transporters by a factor of at least five usingthe scintillation proximity assays as described below.

Generation of Stable Cell-Lines Expressing the Human Dopamine,Norepinephrine and Serotonin Transporters

Standard molecular cloning techniques were used to generate stablecell-lines expressing the human dopamine, norepinephrine and serotonintransporters. The polymerase chain reaction (PCR) was used in order toisolate and amplify each of the three full-length cDNAs from anappropriate cDNA library. Primers for PCR were designed using thefollowing published sequence data:

Human dopamine transporter: GenBank M95167. Reference: Vandenbergh D J,Persico A M and Uhl G R. A human dopamine transporter cDNA predictsreduced glycosylation, displays a novel repetitive element and providesracially-dimorphic TaqI RFLPs. Molecular Brain Research (1992) volume15, pages 161-166.

Human norepinephrine transporter: GenBank M65105. Reference: PacholczykT, Blakely, R D and Amara S G. Expression cloning of a cocaine-andantidepressant-sensitive human noradrenaline transporter. Nature (1991)volume 350, pages 350-354.

Human serotonin transporter: GenBank L05568. Reference: Ramamoorthy S,Bauman A L, Moore K R, Han H, Yang-Feng T, Chang A S, Ganaphthy V andBlakely R D. Antidepressant-and cocaine-sensitive human serotonintransporter: Molecular cloning, expression, and chromosomallocalization. Proceedings of the National Academy of Sciences of the USA(1993) volume 90, pages 2542-2546.

The PCR products were cloned into a mammalian expression vector (egpcDNA3.1 (Invitrogen)) using standard ligation techniques. Theconstructs were then used to stably transfect HEK293 cells using acommercially available lipofection reagent (Lipofectamine™—Invitrogen)following the manufacture's protocol.

Scintillation Proximity Assays for Determining the Affinity of TestLigands at the Norepinephrine Transporter.

The compounds of the present invention are norepinephrine reuptakeinhibitors, and possess excellent activity in, for example, ascintillation proximity assay (e.g. J. Gobel, D. L. Saussy and A. Goetz,J. Pharmacol. Toxicolo. (1999), 42, 237-244). Thus ³H-nisoxetine bindingto norepinephrine re-uptake sites in a cell line transfected with DNAencoding human norepinephrine transporter binding protein has been usedto determine the affinity of ligands at the norepinephrine transporter.

Membrane Preparation:

Cell pastes from large scale production of HEK-293 cells expressingcloned human norepinephrine transporters were homogenized in 4 volumes50 mM Tris-HCl containing 300 mM NaCl and 5 mM KCl, pH 7.4. Thehomogenate was centrifuged twice (40,000 g, 10 min, 4° C.) with pelletre-suspension in 4 volumes of Tris-HCl buffer containing the abovereagents after the first spin and 8 volumes after the second spin. Thesuspended homogenate was centrifuged (10 g, 10 min, 4° C.) and thesupernatant kept and re-centrifuged (40,000 g, 20 min, 4° C.). Thepellet was resuspended in Tris-HCl buffer containing the above reagentsalong with 10% w/v sucrose and 0.1 mM phenylmethylsulfonyl fluoride(PMSF). The membrane preparation was stored in aliquots (1 ml) at −80°C. until required. The protein concentration of the membrane preparationwas determined using a bicinchoninic acid (BCA) protein assay reagentkit (available from Pierce).

[³]-Nisoxetine Binding Assay:

Each well of a 96 well microtitre plate was set up to contain thefollowing:

-   50 μl 2 nM [N-methyl-³H]-Nisoxetine hydrochloride (70-87 Ci/mmol,    from NEN life Science Products)-   75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 300 mM NaCl and    5 mM KCl)-   25 μl Test compound, assay buffer (total binding) or 10 μM    Desipramine HCl (non-specific binding)-   50 μl Wheatgerm agglutinin coated poly (vinyltoluene) (WGA PVT) SPA    Beads (Amersham Biosciences RPNQ0001) (10 mg/ml)-   50 μl Membrane (0.2 mg protein per ml)

The microtitre plates were incubated at room temperature for 10 hoursprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki values for each of the testcompounds.

Serotonin Binding Assay

The ability of a test compound to compete with [³H]-citalopram for itsbinding sites on cloned human serotonin transporter containing membraneshas been used as a measure of test compound ability to block serotoninuptake via its specific transporter (Ramamoorthy, S., Giovanetti, E.,Qian, Y., Blakely, R., (1998) J. Biol. Chem. 273, 2458).

Membrane Preparation:

Membrane preparation is essentially similar to that for thenorepinephrine transporter containing membranes as described above. Themembrane preparation was stored in aliquots (1 ml) at −70° C. untilrequired. The protein concentration of the membrane preparation wasdetermined using a BCA protein assay reagent kit.

[³H]-Citalopram Binding Assay:

Each well of a 96 well microtitre plate was set up to contain thefollowing:

-   50 μl 2 nM [³H]-Citalopram (60-86 Ci/mmol, Amersham Biosciences)-   75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 150 mM NaCl and    5 mM KCl)-   25 μl Diluted compound, assay buffer (total binding) or 100 μM    Fluoxetine (non-specific binding)-   50 μl WGA PVT SPA Beads (40 mg/ml)-   50 μl Membrane preparation (0.4 mg protein per ml)

The microtitre plates were incubated at room temperature for 10 hoursprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki (nM) values for each of theunknown compounds.

Dopamine Binding Assay

The ability of a test compound to compete with [³H]-WIN35,428 for itsbinding sites on human cell membranes containing cloned human dopaminetransporter has been used as a measure of the ability of such testcompounds to block dopamine uptake via its specific transporter(Ramamoorthy et al 1998 supra).

Membrane Preparation:

Is essentially the same as for membranes containing cloned humanserotonin transporter as described above.

[³H]-WIN35,428 Binding Assay:

Each well of a 96well microtitre plate was set up to contain thefollowing:

-   50 μl 4 nM [³H]-WIN35,428 (84-87 Ci/mmol, from NEN Life Science    Products)-   75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 150 mM NaCl and    5 mM KCl)-   25 μl Diluted compound, assay buffer (total binding) or 100 μM    Nomifensine (non-specific binding)-   50 μl WGA PVT SPA Beads (10 mg/ml)-   50 μl Membrane preparation (0.2 mg protein per ml.)

The microtitre plates were incubated at room temperature for 120 minutesprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki values for each of the unknowncompounds.

In Vitro Determination of the Interaction of Compounds with CYP2D6 inHuman Hepatic Microsomes

Cytochrome P450 2D6 (CYP2D6) is a mammalian enzyme which is commonlyassociated with the metabolism of around 30% of pharmaceuticalcompounds. Moreover, this enzyme shows a genetic polymorphism with as aconsequence a presence in the population of poor and normalmetabolizers. A low involvement of CYP2D6 in the metabolism of compounds(i.e. the compound being a poor substrate of CYP2D6) is desirable inorder to reduce any variability from subject to subject in thepharmacokinetics of the compound. Also, compounds with a low inhihibitorpotential for CYP2D6 are desirable in order to avoid drug-druginteractions with co-administered drugs that are substrates of CYP2D6.Compounds may be tested both as substrates and as inhibitors of thisenzyme by means of the following assays.

CYP2D6 Substrate Assay

Principle:

This assay determines the extent of the CYP2D6 enzyme involvement in thetotal oxidative metabolism of a compound in microsomes. Preferredcompounds of the present invention exhibit less than 75% totalmetabolism via the CYP2D6 pathway.

For this in vitro assay, the extent of oxidative metabolism in humanliver microsomes (HLM) is determined after a 30 minute incubation in theabsence and presence of Quinidine, a specific chemical inhibitor ofCYP2D6. The difference in the extent of metabolism in absence andpresence of the inhibitor indicates the involvement of CYP2D6 in themetabolism of the compound.

Materials and Methods:

Human liver microsomes (mixture of 20 different donors, mixed gender)were acquired from Human Biologics (Scottsdale, Ariz., USA). Quinidineand β-NADPH (β-Nicotinamide Adenine Dinucleotide Phosphate, reducedform, tetrasodium salt) were purchased from Sigma (St Louis, Mo., USA).All the other reagents and solvents were of analytical grade. A stocksolution of the new chemical entity (NCE) was prepared in a mixture ofAcetonitrile/Water to reach a final concentration of acetonitrile in theincubation below 0.5%.

The microsomal incubation mixture (total volume 0.1 mL) contained theNCE (4 μM), β-NADPH (1 mM), microsomal proteins (0.5 mg/mL), andQuinidine (0 or 2 μM) in 100 mM sodium phosphate buffer pH 7.4. Themixture was incubated for 30 minutes at 37° C. in a shaking waterbath.The reaction was terminated by the addition of acetonitrile (75 μL). Thesamples were vortexed and the denaturated proteins were removed bycentrifugation. The amount of NCE in the supernatant was analyzed byliquid chromatography/mass spectrometry (LC/MS) after addition of aninternal standard. A sample was also taken at the start of theincubation (t=0), and analysed similarly.

Analysis of the NCE was performed by liquid chromatography/massspectrometry. Ten μL of diluted samples (20 fold dilution in the mobilephase) were injected onto a Spherisorb CN Column, 5 μM and 2.1 mm×100 mm(Waters corp. Milford, Mass., USA). The mobile phase consisting of amixture of Solvent A/Solvent B, 30/70 (v/v) was pumped (Alliance 2795,Waters corp. Milford, Mass., USA) through the column at a flow rate of0.2 ml/minute. Solvent A and Solvent B were a mixture of ammoniumformate 5.10⁻³ M pH 4.5/methanol in the proportions 95/5 (v/v) and 10/90(v/v), for solvent A and solvent B, respectively. The NCE and theinternal standard were quantified by monitoring their molecular ionusing a mass spectrometer ZMD or ZQ (Waters-Micromass corp, Machester,UK) operated in a positive electrospray ionisation.

The extent of CYP2D6 involvement (% of CYP2D6 involvement) wascalculated comparing the extent of metabolism in absence and in presenceof quinidine in the incubation.

The extent of metabolism without inhibitor (%) was calculated asfollows: $\frac{\begin{matrix}{{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right){time}\quad 0} -} \\{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right){time}\quad 30}\end{matrix}}{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right){time}\quad 0} \times 100$

The extent of metabolism with inhibitor (%) was calculated as follows:$\frac{\begin{matrix}{{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right){time}\quad 0} -} \\{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{with}\quad{inhibitor}} \right){time}\quad 30}\end{matrix}}{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right){time}\quad 0} \times 100$where the NCE response is the area of the NCE divided by the area of theinternal standard in the LC/MS analysis chromatogram, time0 and time30correspond to the 0 and 30 minutes incubation time.

The % of CYP2D6 involvement was calculated as follows:$\frac{\begin{matrix}{\left( {\%\quad{extent}\quad{of}\quad{metabolism}\quad{without}\quad{inhibitor}} \right) -} \\\left( {\%\quad{extent}\quad{of}\quad{metabolism}\quad{with}\quad{inhibitor}} \right)\end{matrix}}{\%\quad{extent}\quad{of}\quad{metabolism}\quad{without}\quad{inhibitor}} \times 100$CYP2D6 Inhibitor AssayPrinciple:

The CYP2D6 inhibitor assay evaluates the potential for a compound toinhibit CYP2D6. This is performed by the measurement of the inhibitionof the bufuralol 1′-hydroxylase activity by the compound compared to acontrol. The 1′-hydroxylation of bufuralol is a metabolic reactionspecific to CYP2D6. Preferred compounds of the present invention exhibitan IC₅₀ higher than 6 μM for CYP2D6 activity, the IC₅₀ being theconcentration of the compound that gives 50% of inhibition of the CYP2D6activity.

Material and Methods:

Human liver microsomes (mixture of 20 different donors, mixed gender)were acquired from Human Biologics (Scottsdale, Ariz.). β-NADPH waspurchased from Sigma (St Louis, Mo.). Bufuralol was purchased fromUltrafine (Manchester, UK). All the other reagents and solvents were ofanalytical grade.

Microsomal incubation mixture (total volume 0.1 mL) contained bufuralol10 μM, β-NADPH (2 mM), microsomal proteins (0.5 mg/mL), and the newchemical entity (NCE) (0, 5, and 25 μM) in 100 mM sodium phosphatebuffer pH 7.4. The mixture was incubated in a shaking waterbath at 37°C. for 5 minutes. The reaction was terminated by the addition ofmethanol (75 μL). The samples were vortexed and the denaturated proteinswere removed by centrifugation. The supernatant was analyzed by liquidchromatography connected to a fluorescence detector. The formation ofthe 1′-hydroxybufuralol was monitored in control samples (0 μM NCE) andin the samples incubated in presence of the NCE. The stock solution ofNCE was prepared in a mixture of Acetonitrile/Water to reach a finalconcentration of acetonitrile in the incubation below 1.0%.

The determination of 1′-hydroxybufuralol in the samples was performed byliquid chromatograhy with fluorimetric detection as described below.Twenty five μL samples were injected onto a Chromolith PerformanceRP-18e column (100 mm×4.6 mm) (Merck KGAa, Darmstadt, Germany). Themobile phase, consisting of a mixture of solvent A and solvent B whosethe proportions changed according the following linear gradient, waspumped through the column at a flow rate of 1 ml/min: Time (minutes)Solvent A (%) Solvent B (%) 0 65 35 2.0 65 35 2.5 0 100 5.5 0 100 6.0 6535

Solvent A and Solvent B consisted of a mixture of 0.02 M potassiumdihydrogenophosphate buffer pH3/methanol in the proportion 90/10 (v/v)for solvent A and 10/90 (v/v) for solvent B. The run time was 7.5minutes. Formation of 1′-hydroxybufuralol was monitored by fluorimetricdetection with extinction at λ 252 nm and emission at λ 302 nm.

The IC₅₀ of the NCE for CYP2D6 was calculated by the measurement of thepercent of inhibition of the formation of the 1′-hydroxybufuralol inpresence of the NCE compared to control samples (no NCE) at a knownconcentration of the NCE.

The percent of inhibition of the formation of the 1′-hydroxybufuralol iscalculated as follows: $\frac{\begin{matrix}{\left( {1^{\prime}\text{-}{hydroxybufuralol}\quad{formed}\quad{without}\quad{inhibitor}} \right) -} \\\left( {1^{\prime}\text{-}{hydroxybufuralol}{\quad\quad}{formed}\quad{with}\quad{inhibitor}} \right)\end{matrix}}{\left( {1^{\prime}\text{-}{hydroxybufuralol}\quad{area}\quad{formed}\quad{without}\quad{inhibitor}} \right)} \times 100$

The IC₅₀ is calculated from the percent inhibition of the formation ofthe 1′-hydroxybufuralol as follows (assuming competitive inhibition):$\frac{{NCE}\quad{Concentration} \times \left( {100 - {{Percent}\quad{of}\quad{inhibition}}} \right)}{{Percent}\quad{of}\quad{inhibition}}$

The IC₅₀ estimation is assumed valid if inhibition is between 20% and80% (Moody G C, Griffin S J, Mather A N, McGinnity D P, Riley R J. 1999.Fully automated analysis of activities catalyzed by the major humanliver cytochrome P450 (CYP) enzymes: assessment of human CYP inhibitionpotential. Xenobiotica, 29(1): 53-75).

X-Ray Crystallographic Data for the Compound of Example 1

TABLE 1 Crystal data and structure refinement for 2003xf. Identificationcode 2003xf Empirical formula C18H19ClF3NOS Formula weight 389.85Temperature 107(2) K Wavelength 0.71073 A Crystal system, space groupMonoclinic, P2(1) Unit cell dimensions a = 9.984(2) A alpha = 90 deg. b= 5.6484(13) A beta = 100.867(4) deg. c = 15.931(4) A gamma = 90 deg.Volume 882.4(4) A{circumflex over ( )}3 Z, Calculated density 2, 1.467Mg/m{circumflex over ( )}3 Absorption coefficient 0.371 mm{circumflexover ( )}−1 F(000) 404 Crystal size .06 × .08 × .18 mm Theta range fordata collection 1.30 to 28.20 deg. Limiting indices 11 <= h <= 13, −7 <=k <= 7, −20 <= l <= 19 Reflections collected/unique 5986/3378 [R(int) =0.0661] Completeness to theta = 28.20 92.9% Absorption correction NoneRefinement method Full-matrix least-squares on F{circumflex over ( )}2Data/restraints/parameters 3378/1/234 Goodness-of-fit on F{circumflexover ( )}2 0.846 Final R indices [I > 2sigma(i)] R1 = 0.0488, wR2 =0.0908 R indices (all data) R1 = 0.1227, wR2 = 0.1101 Absolute structureparameter 0.11(10) Largest diff. peak and hole 0.548 and −0.444e.A{circumflex over ( )}−3

X-Ray Crystallographic Data for the Compound of Example 1

TABLE 2 Atomic coordinates (× 10{circumflex over ( )}4) and equivalentisotropic displacement parameters (A{circumflex over ( )}2 ×10{circumflex over ( )}3) for 2003xf. U(eq) is defined as one third ofthe trace of the orthogonalized Uij tensor. x y z U(eq) S(8)  8641(1)5291(2) 2641(1) 35(1) O(1) 10279(3) 2645(5) 4200(2) 24(1) C(7)  9992(5)3088(8) 2678(3) 25(1) F(3)  5136(4) 4842(7)  443(2) 65(1) N(4) 13055(4)1352(9) 4386(3) 21(1) C(5) 12147(4) 1431(8) 3536(3) 22(1) F(2)  7264(4)4253(5)  644(2) 51(1) C(20) 10490(5) 1794(8) 1263(3) 31(1) F(1)  6497(4)7227(5) 1228(2) 48(1) C(15) 10669(5) 3416(8) 1925(3) 24(1) C(6) 11008(5)3187(8) 3525(3) 24(1) C(16) 11472(5)  5394(10) 1846(3) 32(1) C(10) 6184(5) 3389(9) 1805(3) 26(1) C(13)  5978(5)  382(11) 3117(4) 40(1)C(9)  7190(5) 3438(9) 2506(3) 30(1) C(3) 12283(5)  976(8) 5085(3) 27(1)C(12)  4992(5)  364(10) 2423(3) 31(1) C(2) 11168(5) 2787(9) 5010(3)28(1) C(21)  6253(6)  4934(11) 1033(4) 41(2) C(18) 11846(5)  4080(10) 494(3) 33(1) C(17) 12048(5) 5721(9) 1131(4) 36(1) C(19) 11078(5)2138(9)  552(4) 35(1) C(11)  5062(5) 1943(9) 1738(4) 42(2) C(14) 7065(6)  1852(10) 3160(4) 43(2) Cl(1)  4131(1) 6360(2) 4214(1) 30(1)

X-Ray Crystallographic Data for the Compound of Example 1

TABLE 3 Bond lengths [A] and angles [deg] for 2003xf. S(8)—C(9) 1.767(5)S(8)—C(7) 1.828(5) O(1)—C(2) 1.424(5) O(1)—C(6) 1.440(5) C(7)—C(15)1.495(6) C(7)—C(6) 1.528(6) F(3)—C(21) 1.318(6) N(4)—C(5) 1.481(5)N(4)—C(3) 1.484(6) C(5)—C(6) 1.507(6) F(2)—C(21) 1.337(6) C(20)—C(19)1.385(7) C(20)—C(15) 1.383(6) F(1)—C(21) 1.343(6) C(15)—C(16) 1.395(6)C(16)—C(17) 1.382(7) C(10)—C(9) 1.354(6) C(10)—C(11) 1.374(7)C(10)—C(21) 1.520(8) C(13)—C(12) 1.334(6) C(13)—C(14) 1.358(7)C(9)—C(14) 1.397(7) C(3)—C(2) 1.500(6) C(12)—C(11) 1.421(7) C(18)—C(19)1.351(7) C(18)—C(17) 1.360(7) C(9)—S(8)—C(7) 100.6(2) C(2)—O(1)—C(6)110.4(4) C(15)—C(7)—C(6) 112.3(4) C(15)—C(7)—S(8) 109.4(3)C(6)—C(7)—S(8) 111.5(3) C(5)—N(4)—C(3) 112.0(4) N(4)—C(5)—C(6)  11.2(4)C(19)—C(20)—C(15) 121.2(5) C(20)—C(15)—C(16) 117.1(5) C(20)—C(15)—C(7)121.1(5) C(16)—C(15)—C(7) 121.8(5) O(1)—C(6)—C(5) 109.7(4)O(1)—C(6)—C(7) 107.9(4) C(5)—C(6)—C(7) 111.1(4) C(17)—C(16)—C(15)121.2(5) C(9)—C(10)—C(11) 122.9(5) C(9)—C(10)—C(21) 121.0(5)C(11)—C(10)—C(21) 116.0(5) C(12)—C(13)—C(14) 120.3(6) C(10)—C(9)—C(14)116.4(5) C(10)—C(9)—S(8) 125.2(4) C(14)—C(9)—S(8) 118.4(4)N(4)—C(3)—C(2) 109.0(4) C(13)—C(12)—C(11) 119.7(5) O(1)—C(2)—C(3)111.1(4) F(3)—C(21)—F(1) 107.1(5) F(3)—C(21)—F(2) 105.6(5)F(1)—C(21)—F(2) 105.4(5) F(3)—C(21)—C(10) 113.2(5) F(1)—C(21)—C(10)113.6(5) F(2)—C(21)—C(10) 111.4(5) C(19)—C(18)—C(17) 120.6(5)C(18)—C(17)—C(16) 119.8(5) C(18)—C(19)—C(20) 120.2(5) C(10)—C(11)—C(12)118.1(5) C(13)—C(14)—C(9) 122.5(5)

Symmetry transformations used to generate equivalent atoms:

X-Ray Crystallographic Data for the Compound of Example 1

TABLE 4 Anisotropic displacement parameters (A{circumflex over ( )}2 ×10{circumflex over ( )}3) for 2003xf. The anisotropic displacementfactor exponent takes the form: −2 pi{circumflex over ( )}2[h{circumflex over ( )}2 a*{circumflex over ( )}2 U11 + . . . + 2 h k a*b* U12] U11 U22 U33 U23 U13 U12 S(8) 24(1) 24(1) 53(1) −1(1) −1(1) 4(1)O(1) 24(2) 23(2) 24(2) 3(2) 0(2) −2(2) C(7) 20(3) 23(2) 27(3) −3(2)−8(3) 0(2) F(3) 55(2) 88(3) 42(2) 15(2) −16(2) −13(2) N(4) 19(2) 14(2)31(3) 3(2) 3(2) −3(3) C(5) 22(3) 16(2) 26(3) −4(2) 2(2) 2(3) F(2) 69(3)53(2) 39(2) 5(2) 29(2) 3(2) C(20) 29(3) 28(3) 31(3) −12(3) −5(3) −1(2)F(1) 61(2) 35(2) 46(2) 5(2) 5(2) 5(2) C(15) 20(3) 22(3) 27(3) 2(3) −3(2)5(2) C(6) 23(3) 17(2) 33(3) −1(2) 11(3) 1(2) C(16) 40(3) 22(2) 31(3)−3(3) 1(3) −7(3) C(10) 20(3) 30(3) 27(3) 2(3) 8(3) 4(3) C(13) 33(3)45(3) 42(4) 3(3) 7(3) 0(3) C(9) 20(3) 38(3) 31(4) −8(3) 2(3) 7(3) C(3)22(3) 28(3) 32(3) 10(2) 5(2) 0(2) C(12) 22(3) 29(2) 41(4) −1(3) 8(3)−7(3) C(2) 28(3) 34(3) 22(3) −2(3) 3(3) 4(2) C(21) 27(4) 50(4) 43(4)−16(3) −1(3) 10(3) C(18) 24(3) 44(3) 30(4) −1(3) 3(3) 11(3) C(17) 42(4)26(3) 40(4) 0(3) 9(3) −6(2) C(19) 33(3) 38(3) 33(4) −9(3) 2(3) 6(3)C(11) 20(3) 49(4) 52(4) −18(3) −3(3) 8(3) C(14) 35(4) 72(5) 22(3) 16(3)−1(3) −4(3) Cl(1) 24(1) 16(1) 46(1) 1(1) −1(1) −1(1)

X-Ray Crystallographic Data for the Compound of Example 1

TABLE 5 Hydrogen coordinates (× 10{circumflex over ( )}4) and isotropicdisplacement parameters (A{circumflex over ( )}2 × 10{circumflex over( )}3) for 2003xf. x y z U(eq) H(7A)  9558 1486 2630 30 H(5A) 11757 −1623392 26 H(5B) 12685 1877 3099 26 H(20A)  9954   420 1297 37 H(6A) 113984819 3611 29 H(16A) 11626 6536 2292 38 H(13A)  5919 −637 3583 48 H(3A)12902 1128 5645 33 H(3B) 11886 −636 5043 33 H(12A)  4246 −700 2387 37H(2A) 10639 2529 5468 34 H(2B) 11575 4389 5085 34 H(18A) 12248 4302   540 H(17A) 12584 7087 1084 43 H(19A) 10941 1005  103 42 H(11A)  4354 19981248 50 H(14A)  7767 1799 3653 52 H(4B) 13680(60) 2600(100) 4430(30)53(19) H(4A) 13580(50)  230(90) 4400(30) 29(17)

X-Ray Crystallographic Data for the Compound of Example 1

TABLE 6 Torsion angles [deg] for 2003xf. C(9)—S(8)—C(7)—C(15)   115.5(4)C(9)—S(8)—C(7)—C(6) −119.7(4) C(3)—N(4)—C(5)—C(6)    52.2(6)C(19)—C(20)—C(15)—C(16)  −0.4(7) C(19)—C(20)—C(15)—C(7)   177.8(4)C(6)—C(7)—C(15)—C(20)   126.4(5) S(8)—C(7)—C(15)—C(20) −109.2(4)C(6)—C(7)—C(15)—C(16)  −55.5(6) S(8)—C(7)—C(15)—C(16)    68.9(5)C(2)—O(1)—C(6)—C(5)    60.7(5) C(2)—O(1)—C(6)—C(7) −178.1(4)N(4)—C(5)—C(6)—O(1)  −55.1(5) N(4)—C(5)—C(6)—C(7) −174.3(4)C(15)—C(7)—C(6)—O(1) −175.0(4) S(8)—C(7)—C(6)—O(1)    61.9(4)C(15)—C(7)—C(6)—C(5)  −54.7(5) S(8)—C(7)—C(6)—C(5) −177.8(3)C(20)—C(15)—C(16)—C(17)    0.7(7) C(7)—C(15)—C(16)—C(17) −177.4(5)C(11)—C(10)—C(9)—C(14)    2.6(8) C(21)—C(10)—C(9)—C(14) −176.4(5)C(11)—C(10)—C(9)—S(8) −178.8(4) C(21)—C(10)—C(9)—S(8)    2.2(7)C(7)—S(8)—C(9)—C(10) −114.6(5) C(7)—S(8)—C(9)—C(14)    64.0(5)C(5)—N(4)—C(3)—C(2)  −52.6(6) C(14)—C(13)—C(12)—C(11)  −1.9(8)C(6)—O(1)—C(2)—C(3)  −63.3(5) N(4)—C(3)—C(2)—O(1)    58.2(5)C(9)—C(10)—C(21)—F(3) −173.8(5) C(11)—C(10)—C(21)—F(3)    7.1(7)C(9)—C(10)—C(21)—F(1)  −51.3(7) C(11)—C(10)—C(21)—F(1)   129.6(5)C(9)—C(10)—C(21)—F(2)    67.4(7) C(11)—C(10)—C(21)—F(2) −111.6(5)C(19)—C(18)—C(17)—C(16)    0.5(8) C(15)—C(16)—C(17)—C(18)  −0.7(8)C(17)—C(18)—C(19)—C(20)  −0.2(8) C(15)—C(20)—C(19)—C(18)    0.1(8)C(9)—C(10)—C(11)—C(12)  −2.7(8) C(21)—C(10)—C(11)—C(12)   176.3(5)C(13)—C(12)—C(11)—C(10)    2.3(8) C(12)—C(13)—C(14)—C(9)    1.9(8)C(10)—C(9)—C(14)—C(13)  −2.1(8) S(8)—C(9)—C(14)—C(13)   179.2(4)

Symmetry transformations used to generate equivalent atoms

1. A compound of formula (I):

wherein: A is S or O; R is H; Ar is a phenyl group optionallysubstituted with 1, 2, 3, 4 or 5 substituents each independentlyselected from C₁-C₄ alkyl, O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo,hydroxy, CO₂(C₁-C₄ alkyl), pyridyl, thiophenyl and phenyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents each independentlyselected from halo, C₁-C₄ alkyl, or O(C₁-C₄ alkyl); X is a phenyl groupoptionally substituted with 1, 2, 3, 4 or 5 substituents eachindependently selected from halo, C₁-C₄ alkyl, or O(C₁-C₄ alkyl); aC₁-C₄ alkyl group; a C₃-C₆ cycloalkyl group or a CH₂(C₃-C₆ cycloalkyl)group; R′ is H or C₁-C₄ alkyl; each R¹ is independently H or C₁-C₄alkyl; wherein each above-mentioned C₁-C₄ alkyl group is optionallysubstituted with one or more halo atoms; or a pharmaceuticallyacceptable salt thereof; with the proviso that, when A is 0, X is aC₁-C₄ alkyl group, a C₃-C₆ cycloalkyl group or a CH₂(C₃-C₆ cycloalkyl)group.
 2. A compound of claim 1, where A is S.
 3. A compound of formula(Ia):

wherein: R is H; Ar is a phenyl group optionally substituted with 1, 2,3, 4 or 5 substituents each independently selected from C₁-C₄ alkyl,O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo, and phenyl optionally substitutedwith substituents each independently selected from halo, C₁-C₄ alkyl, orO(C₁-C₄ alkyl); X is a phenyl group optionally substituted with 1, 2, 3,4 or 5 substituents each independently selected from halo, C₁-C₄ alkyl,or O(C₁-C₄ alkyl); R′ is H or C₁-C₄ alkyl; each R¹ is independently H orC₁-C₄ alkyl; wherein each above-mentioned C₁-C₄ alkyl group isoptionally substituted with one or more halo atoms; and pharmaceuticallyacceptable salts thereof.
 4. A compound of claim 1, represented byformula (II):

wherein: R₂ and R₃ are each independently selected from H, C₁-C₄ alkyl,O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo, and phenyl; and R₄ is selectedfrom H and C₁-C₄ alkyl; wherein each above-mentioned C₁-C₄ alkyl groupis optionally substituted with one or more halo atoms; andpharmaceutically acceptable salts thereof.
 5. A compound of claim 4,wherein R₂ is selected from C₁-C₄ alkyl, O(C₁-C₄ alkyl), F, and Ph,wherein each above-mentioned C₁-C₄ alkyl group is optionally substitutedwith one or more halo atoms.
 6. A compound of claim 4, wherein R₃ ishydrogen.
 7. A compound of claim 4, wherein R₄ is hydrogen.
 8. A methodof preparing a compound of claim 1, comprising reacting a compound ofthe formula (III):

where R₅ is a protecting group, X, R′ and R1 are as defined in formula(I), and Y is a leaving group, with an aryl thiol or hydroxy arylcompound.
 9. A method of preparing a compound of claim 1, comprisingdeprotecting a compound of the formula (IV):

where R₅ is a protecting group and A, Ar, X, R′ and R¹ are as defined informula (I) to provide a compound of formula (I), optionally followed bythe step of forming a pharmaceutically acceptable salt. 10-13.(canceled)
 14. A method for selectively inhibiting the reuptake ofnorepinephrine in mammals, comprising administering to a patient in needthereof an effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 15. A method for treatingdisorders associated with norepinephrine dysfunction in mammals,comprising administering to a patient in need thereof an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 16. (canceled)
 17. A method of claim 15, wherein the disorderis attention-deficit hyperactivity disorder.
 18. A compositionscomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable diluent, excipient,or carrier.